Compositions and methods for cancer treatment
阅读说明：本技术 用于癌症治疗的组合物和方法 (Compositions and methods for cancer treatment ) 是由 M.S.戈尔德伯格 于 2019-03-20 设计创作，主要内容包括：本申请提供了可用于治疗和/或预防癌症和转移肿瘤的药物递送组合物和器件。例如,提供了包含可生物降解的支架或生物材料的药物递送组合物和/或器件,该可生物降解的支架或生物材料包含抑制一种或多种促炎途径的一种或多种药剂,所述促炎途径为如由p38丝裂原激活的蛋白激酶(MAPK)途径介导的一种或多种免疫反应。在一些实施方式中,药物递送组合物和/或器件可进一步包含激活先天免疫系统的药剂(例如,STING激动剂)和/或激活适应性免疫系统的一种或多种药剂(例如,抗PD-1抗体)。在一些实施方式中,药物递送组合物和/或器件可包含细胞因子(例如,IL-15超激动剂)。在一些实施方式中,药物递送组合物和/或器件可被施用到肿瘤切除部位(例如,因肿瘤切除所致的空隙体积)。这样的术中施用可预防肿瘤再生长和/或肿瘤转移。还提供了制备药物递送组合物和器件的方法以及包含提供其的材料的试剂盒。(The present application provides drug delivery compositions and devices useful for the treatment and/or prevention of cancer and metastatic tumors. For example, drug delivery compositions and/or devices are provided comprising a biodegradable scaffold or biomaterial comprising one or more agents that inhibit one or more pro-inflammatory pathways, such as one or more immune responses mediated by the p38 mitogen-activated protein kinase (MAPK) pathway. In some embodiments, the drug delivery compositions and/or devices may further comprise an agent that activates the innate immune system (e.g., a STING agonist) and/or one or more agents that activate the adaptive immune system (e.g., an anti-PD-1 antibody). In some embodiments, the drug delivery compositions and/or devices can comprise a cytokine (e.g., an IL-15 superagonist). In some embodiments, the drug delivery composition and/or device can be administered to a tumor resection site (e.g., void volume due to tumor resection). Such intraoperative administration can prevent tumor regrowth and/or tumor metastasis. Also provided are methods of making drug delivery compositions and devices and kits comprising materials that provide the same.)
1. A method comprising the steps of:
administering in a tumor resection site procedure of a subject having cancer:
a composition comprising a biomaterial and an inhibitor of a pro-inflammatory immune response mediated by the p38 mitogen-activated protein kinase (MAPK) pathway.
2. The method of claim 1, wherein the biomaterial is characterized by a storage modulus of about 500Pa to about 50,000 Pa.
3. The method of claim 1, wherein the administering step does not involve adoptive transfer of T cells to the subject.
4. The method of claim 1, wherein the administering step does not involve administering a tumor antigen to the subject.
5. The method of claim 1, wherein the administering step does not involve administering microparticles to the subject.
6. The method of claim 1, wherein the biological material is or comprises a hydrogel.
7. The method of claim 6, wherein the biological material is or comprises hyaluronic acid.
8. The method of claim 7, wherein the biological material is or comprises cross-linked hyaluronic acid.
9. The method of claim 8, wherein the biomaterial is or comprises hyaluronic acid cross-linked with a polyethylene glycol cross-linking agent.
10. The method of claim 1, wherein the inhibitor is or comprises a p38 MAPK inhibitor that binds to an allosteric binding site of ATP and/or p38 MAPK.
11. The method of claim 1, wherein the inhibitor is or comprises a p38 a/β MAPK inhibitor that binds to an allosteric binding site of ATP and/or p38 MAPK.
12. The method of claim 11, wherein the p38 a/p MAPK inhibitor is or comprises loshapimod.
13. The method of claim 1, wherein the composition further comprises an innate immune activator.
14. The method of claim 13, wherein the innate immune activator is or comprises an agonist of an interferon gene Stimulator (STING).
15. The method of claim 13, wherein the innate immune activator is or comprises a Toll-like receptor (TLR)7 and/or TLR8 ("TLR 7/8") agonist.
16. The method of claim 1, wherein the composition further comprises an adaptive immune activator and/or a cytokine that modulates T cells, Natural Killer (NK) cells, monocytes, and/or dendritic cells.
17. The method of claim 1, wherein the composition further comprises cytokines that regulate T cells, NK cells, monocytes, and/or dendritic cells; and the cytokine is selected from the group consisting of IL-15 superagonists, IFN-alpha, IFN-beta, IFN-gamma and combinations thereof.
18. The method of claim 1, wherein said composition further comprises a COX inhibitor.
19. The method of claim 1, wherein said composition further comprises a COX-2 inhibitor.
20. The method of claim 1, wherein the biomaterial forms a matrix or reservoir and the inhibitor is in the biomaterial.
21. The method of claim 20, wherein the inhibitory agent is released by diffusion through the biological material.
22. The method of claim 1, wherein the biomaterial is biodegradable in vivo.
23. The method of claim 1, wherein the biomaterial is characterized by having less than or equal to 10% of the biomaterial remaining in vivo 4 months after implantation when tested in vivo by implanting the biomaterial on a pad of milk fat in a mouse subject.
24. The method of claim 1, wherein the biomaterial is characterized by releasing less than 100% of the loshapimod from the biomaterial within 3 hours when tested in vitro by placing a composition comprising the biomaterial and the loshapimod in PBS (pH 7.4).
25. The method of claim 1, wherein the biomaterial is characterized by releasing less than or equal to 50% of the loshapimod in vivo at 8 hours post-implantation when tested in vivo by implanting a composition comprising the biomaterial and the loshapimod on a milk fat pad of a mouse subject.
26. The method of claim 1, wherein the biomaterial is characterized in that it prolongs the release of the inhibitor so that there is more inhibitor in the tumor resection site when assessed 24 hours after administration than is observed when the inhibitor is administered in solution.
27. The method of claim 1, wherein the administering is by implantation.
28. The method of claim 1, wherein the administering is by injection.
29. The method of claim 28, wherein the administering comprises injecting one or more precursor components of the biological material and allowing the biological material to form at the tumor resection site.
30. The method of claim 1, wherein the tumor resection site is characterized by an absence of substantial residual tumor antigen.
31. The method of claim 1, wherein the cancer is metastatic cancer.
32. The method of claim 31, further comprising the step of monitoring at least one site of metastasis in the subject after said administering.
Background
Systemic administration of drugs, nutrients or other substances into the circulatory system affects the entire body. Systemic routes of administration include enteral (e.g., oral dosage forms that result in absorption of the drug through the gastrointestinal tract) and parenteral (e.g., intravenous, intramuscular, and subcutaneous injections). Administration of immunotherapeutic drugs is often dependent on these systemic routes of administration, which may lead to undesirable side effects. In some cases, certain promising therapies are extremely difficult to develop due to the associated toxicity and limitations of current methods and systems of administration.
Surgery is often a first-line treatment of solid tumor cancers, often in combination with systemic anti-cancer therapies. However, due to various alterations in metabolic and endocrine responses, surgically-induced immunosuppression is associated with the development of postoperative sepsis complications and tumor metastasis, ultimately leading to death in many patients (Smyth, m.j.et. Nature Reviews clinical oncology, 2016, 13, 143-.
Disclosure of Invention
Systemic administration of immunotherapy can result in adverse side effects, e.g., induction of undesirable toxicity to non-cancerous cells and/or tissues (e.g., non-tumor specific immune cells), and/or require high doses to achieve sufficient concentrations at the target site to induce a therapeutic response; and surgical removal of tumors can lead to immunosuppression. Surgery may also induce cellular stress, which may involve, for example, activating one or more physiological responses that promote wound healing after injury. Such responses include, for example, activation of neural, inflammatory, and/or pro-angiogenic signaling pathways, which may also promote growth and/or metastatic spread of cancer. Inflammatory changes that may occur at the surgical site following tumor resection may include, for example, immune and/or inflammatory cell type recruitment and/or humoral factor release. Local inflammatory wound responses and systemic inflammatory processes may co-activate dormant micrometastases or induce proliferation of residual cancer cells, thereby increasing the risk of cancer recurrence.
The present disclosure provides, among other things, insight that includes identifying sources of problems with certain prior art techniques, including, for example, certain conventional cancer treatment methods. For example, the present disclosure recognizes that certain adverse events that may be associated with systemic administration of immunotherapeutics (e.g., skin rash, hepatitis, diarrhea, colitis, hypophysitis, thyroiditis, and adrenal insufficiency) may be related to immunity and may be due, at least in part, to exposure of non-tumor specific immune cells to systemically administered immunotherapeutic drugs. The present disclosure recognizes, among other things, that high doses, which are typically required for systemic administration to achieve sufficient concentrations in a tumor to induce a desired response, may contribute to and/or cause such adverse effects. The present technology provides a system that addresses these problems by providing local delivery of immunotherapeutic agents that can improve efficacy by focusing the action of the desired drug.
In addition, the present disclosure provides insight that certain immunomodulatory agents that are traditionally used to treat autoimmune-type pathologies can be used in the treatment of cancer, if administered as described herein, but off-target toxicity is expected to occur as opposed to that expected for anti-cancer immunomodulatory compounds. Thus, the present disclosure teaches the availability of agents for cancer therapy that were not previously considered available, and further teaches delivery and administration strategies that are particularly effective and/or desirable for these and other agents.
The present invention recognizes, among other things, that inhibiting one or more pro-inflammatory immune responses at a tumor resection site mediated by the p38 mitogen-activated protein kinase (MAPK) pathway (e.g., by administration of a p38MAPK inhibitor) can reduce the risk of cancer recurrence, thereby extending survival. The present disclosure provides drug delivery systems that can locally deliver one or more immunomodulatory agents to a target site (e.g., a site where a portion of a tumor has been removed and/or where cancer cells have been treated or killed, e.g., by chemotherapy or radiation), thereby focusing the effect of the immunomodulatory agents on the desired target site. Such drug delivery systems may be particularly useful for treating cancer. In particular, the drug delivery system delivers one or more therapeutic agents that act on (e.g., inhibit) one or more pro-inflammatory pathways (e.g., pro-inflammatory immune responses mediated by the p38MAPK pathway; see, e.g., fig. 4-6) to treat cancer, e.g., after tumor resection, such as, e.g., by preventing tumor recurrence and/or metastasis (e.g., delaying onset or reducing extent), while minimizing adverse side effects and/or systemic exposure, in some embodiments.
In some aspects, methods are provided that include administering a composition comprising, in a target site (e.g., tumor resection site) of a subject having cancer: the composition comprises a biomaterial and an inhibitor of a pro-inflammatory immune response mediated by the p38 mitogen-activated protein kinase (MAPK) pathway.
In certain embodiments, the biomaterial has a storage modulus of about 500Pa to about 50,000 Pa. In certain embodiments, the biomaterial is or comprises a hydrogel. In certain embodiments, the biomaterial is or comprises hyaluronic acid. In certain embodiments, the biomaterial is or comprises cross-linked hyaluronic acid. In certain embodiments, the biomaterial is or comprises hyaluronic acid cross-linked with a polyethylene glycol cross-linking agent.
In certain embodiments, the method does not comprise administering adoptive transfer of T cells to the subject. In certain embodiments, the method does not comprise administering a tumor antigen to the subject. In certain embodiments, the method does not comprise administering the microparticle to the subject.
In certain embodiments, the inhibitor is a p38 a/β MAPK inhibitor that binds to an allosteric binding site of ATP and/or p38 MAPK. In certain embodiments, the p38 a/β MAPK inhibitor is loshapimod.
In certain embodiments, the composition further comprises an innate immune activator. In certain embodiments, the innate immune activator is an agonist of an interferon gene Stimulator (STING). In certain embodiments, the innate immune activator is a Toll-like receptor (TLR)7 and/or TLR8 ("TLR 7/8") agonist. In certain embodiments, the composition further comprises an adaptive immune activator and/or a cytokine that modulates T cells, Natural Killer (NK) cells, monocytes, and/or dendritic cells. In certain embodiments, the composition further comprises a cytokine that modulates T cells, NK cells, monocytes, and/or dendritic cells. Examples of such cytokines include, but are not limited to, IL-15 superagonists, IFN- α, IFN- β, IFN- γ, and combinations thereof. In certain embodiments, the compositions further comprise a Cyclooxygenase (COX) inhibitor, including, for example, a COX-2 inhibitor.
It will be appreciated by those skilled in the art that certain COX inhibitors and/or other anti-inflammatory agents (e.g., Non-steroidal anti-inflammatory drugs (NSAIDs) and/or anti-inflammatory analgesics) may be used as modulators (e.g., inhibitors) of the p38 MAPK pathway or components thereof (see, e.g., Esposito et al, "Non-steroidal anti-inflammatory drug delivery in Parkinson's disease" Experimental neural network 205: 295-312 (2007); Desai et al, "Mechanisms of molecular Modulation of cyclic oncogene Di-2 (COX-2) and expressed mutation Cancer" number and Cancer, 70: 350-375 (2018); Huang et al, "MAPK/ERK signal therapy in vitro expression of VEGF-2 bCOX-1 and tissue J1 (Mar et al; Marneed et al: protein inhibition of VEGF-2 protein degradation of VEGF-inflammatory-1 protein degradation of VEGF-2 tissue degradation of VEGF-1 and inhibition of VEGF-2 (proliferation) and expression of protein degradation of VEGF receptor, expression of VEGF-2, 1 and expression of protein degradation of VEGF-2 (Mar 2136; Marmoreover, "HETES enhanced IL-1-mediated COX-2expression administration of message stability in human collagen myoblasts" Am JPhysiol-gastroenterest Liver Physiol, 293: 2092-2101(2007)). Thus, in some embodiments, a COX-2 inhibitor or other anti-inflammatory agent (e.g., a non-steroidal anti-inflammatory drug (NSAID) and/or an anti-inflammatory analgesic) can be (and/or can be used as) a p38 MAPK inhibitor as described herein; alternatively, or additionally, in some embodiments, such COX-2 inhibitors or other anti-inflammatory agents (e.g., anti-inflammatory analgesics) may be used in combination with another p38 MAPK inhibitor described herein.
In certain embodiments, the biomaterial forms a matrix or reservoir and the inhibitor is in the biomaterial. In certain embodiments, the inhibitor is released by diffusion through the biomaterial. In certain embodiments, the biomaterial is biodegradable in vivo. In certain embodiments, the biomaterial is characterized by having less than or equal to 10% of the biomaterial remaining in vivo 4 months after implantation when tested in vivo by implanting the biomaterial on a pad of milk fat in a mouse subject. In certain embodiments, the biomaterial is characterized in that less than 100% of the loshapimod is released from the biomaterial within 3 hours when tested in vitro by placing the composition comprising the biomaterial and the loshapimod in PBS (ph 7.4). In certain embodiments, the biomaterial is characterized by an in vivo release of less than or equal to 50% of the loshapimod at 8 hours post-implantation when tested in vitro by implanting a composition comprising the biomaterial and the loshapimod on a milk fat pad of a mouse subject. In certain embodiments, the biomaterial is characterized in that it prolongs the release of the inhibitor, so that when evaluated 24 hours after administration, there is more inhibitor present in the tumor resection site than is observed when the inhibitor is administered in solution.
In certain embodiments, administration is by implantation. In certain embodiments, administration is by injection. In certain embodiments, administering comprises injecting one or more precursor components of the biomaterial and allowing the biomaterial to form at the tumor resection site. In certain embodiments, when the target site is a tumor resection site, the tumor resection site is characterized by the absence of gross residual tumor antigen (gross residual tumor antigen). In certain embodiments, the cancer is metastatic cancer. In certain embodiments, the method further comprises monitoring at least one site of metastasis in the subject after administration of the composition.
The details of certain embodiments of the invention are set forth herein. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.
Definition of
As used herein, the term "salt" refers to any and all salts, and includes salts.
The term "pharmaceutically acceptable salts" refers to those salts as follows: within the scope of sound medical judgment, are suitable for use with salts that come into contact with tissues such as humans and/or animals without excessive toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art and are described in detail, for example, in J.pharmaceutical sciences,1977,66,1-19 by Berge et al. Pharmaceutically acceptable salts useful according to certain embodiments of the present disclosure may include, for example, those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbic acid Salts, aspartic acid, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, caproates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoate, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, p-benzenesulfonates, undecanoates, pentanoates, and the like. Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and N+(C1-C4Alkyl radical)4 -And (3) salt. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include, if applicable, the non-toxic ammonium, quaternary ammonium and amine cation salts formed using counterions such as hydrohalide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
The term "polymer" is given in its ordinary meaning as used in the art, i.e., a molecular structure comprising one or more repeating units (monomers) linked by covalent bonds. The repeat units may all be the same, or, in some cases, more than one type of repeat unit may also be present in the polymer. In certain embodiments, the polymer is naturally occurring. In certain embodiments, the polymer is synthetic (i.e., not naturally occurring). In some embodiments, the polymer used according to the present disclosure is a polypeptide. In some embodiments, the polymer used according to the present disclosure is a nucleic acid.
The term "bioadhesive" refers to a biocompatible agent that is capable of adhering to a target surface, for example, a tissue surface. In some casesIn embodiments, the bioadhesive may adhere to a target surface, e.g., a tissue surface, and remain on the target surface, e.g., for a period of time in some embodiments, the bioadhesive may be biodegradable. In some embodiments, the bioadhesive may be a natural agent, which may be prepared or obtained, for example, by isolation or by synthesis; in some embodiments, the bioadhesive can be a non-natural agent, for example, as understood by one of skill in the art, has been designed and/or manufactured by the human hand (e.g., by processing, synthesis and/or recombinant production), depending on the agent. In some particular embodiments, the bioadhesive may be or comprise a polymeric material, for example, which may consist of or comprise a plurality of monomers, such as sugars. Certain exemplary bioadhesives include various FDA approved agents, for example, cyanoacrylate (Dermabond, 2-octyl cyanoacrylate; Indermil, n-butyl 2-cyanoacrylate; Histoacryl and Histoacryl Blue, n-butyl 2-cyanoacrylate), albumin, and glutaraldehyde (BioGlue) TMBovine serum albumin and 10% glutaraldehyde), fibrin glue (Tisseel)TMHuman mixed plasma fibrinogen and thrombin; evicelTMHuman mixed plasma fibrinogen and thrombin; vitagelTMAutologous plasma fibrinogen and thrombin; cryosealTMSystems, autologous plasma fibrinogen and thrombin), gelatin and/or resorcinol crosslinked by formaldehyde and/or glutaraldehyde, polysaccharide binders (gelatin, collagen, dextran, chitosan, alginate), PEG, acrylates, polyamines, or polyurethane derivatives (isocyanate-terminated prepolymers, and/or combinations thereof). Other examples of Bioadhesives known in the art may be used for the purposes of the methods described herein, for example, as described in Mehdizadeh and Yang "Design Strategies and Applications of Tissue Bioadhesives" macromolecular biosci 13:271-288 (2013). In some embodiments, the bioadhesive may be a degradable bioadhesive. Examples of such degradable biological adhesives include, but are not limited to, fibrin glue, gelatin-resorcinol-formaldehyde/glutaraldehyde glue, poly (ethylene glycol) (PEG) based hydrogel adhesives, polysaccharide adhesives, polypeptide adhesivesAdhesives, polymeric binders, biomimetic bioadhesives, and the methods described in Bhagat and Becker gradable Adhesives for Surgery and tissue engineering, "Biomacromolecules 18: 3009-3039 (2017).
The term "crosslinker" refers to an agent that links one entity (e.g., one polymer chain) to another entity (e.g., another polymer chain). In some embodiments, the linkage between two entities (i.e., "cross-linking") is or includes a covalent bond. In some embodiments, the linkage between two entities is or includes a non-covalent association. For example, in some embodiments, the linkage between two entities is or includes an ionic bond or an interaction. In some embodiments, the crosslinking agent is a small molecule (e.g., dialdehyde or genipin) for inducing the formation of a covalent bond between the aldehyde and amino group. In some embodiments, the crosslinking agent comprises a photosensitive functional group. In some embodiments, the crosslinking agent comprises a pH-sensitive functional group. In some embodiments, the crosslinking agent comprises a thermally sensitive functional group.
As used herein, the term "solvate" has its art-understood meaning, which refers to an aggregate of a compound (which may be, for example, a salt form of the compound) with one or more solvent atoms or molecules. In some embodiments, the solvate is a liquid. In some embodiments, the solvate is in a solid form (e.g., a crystalline form). In some embodiments, the solvate in solid form is easily isolated. In some embodiments, the association between the solvent atom in the solvate and the compound is a non-covalent association. In some embodiments, such association is or includes hydrogen bonding, van der waals interactions, or a combination thereof. In some embodiments, the solvent whose atoms are included in the solvate may be or include one or more of the following: water, methanol, ethanol, acetic acid, DMSO, THF, ether, and the like. Suitable solvates may be pharmaceutically acceptable solvates; in some particular embodiments, the solvate is a hydrate, an ethanolate, or a methanolate. In some embodiments, the solvate may be a stoichiometric solvate or a non-stoichiometric solvate.
As used herein, the term "hydrate" has its meaning as understood in the art and refers to an aggregate of a compound (which may, for example, be in the form of a salt of the compound) and one or more water molecules. Generally, there is a defined ratio of the number of water molecules contained in the hydrate of the compound to the number of molecules of the compound in the hydrate. Thus, hydrates of the compounds can be prepared, for example, by the formula R. x H2O represents, wherein R is a compound and x is a number greater than 0. A given compound may form more than one type of hydrate, including, for example, monohydrate (x is 1), low hydrate (x is a number greater than 0 and less than 1, e.g., hemihydrate (R0.5H)2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrate (R.2H)2O) and hexahydrate (R.6H)2O))。
The term "tautomer" or "tautomeric" refers to two or more interconvertible compounds resulting from at least one formal migration and at least one change in valence of a hydrogen atom (e.g., single bond to double bond, triple bond to single bond, or vice versa). The exact ratio of tautomers depends on several factors including temperature, solvent and pH. Tautomerization (i.e., the reaction that provides a tautomeric pair) can be catalyzed by either an acid or a base. Exemplary tautomerism includes keto-to-enol, amide-to-imide, lactam-to-lactam-imide, enamine-to-imine, and enamine-to (different enamine) tautomerism.
It is also understood that compounds having the same molecular formula but differing in the nature or order of bonding of their atoms or the arrangement of their atoms in space are referred to as "isomers". Isomers in which the arrangement of atoms in space is different are referred to as "stereoisomers".
The term "polymorph" refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). Many compounds may take a variety of different crystal forms (i.e., different polymorphs). Typically, such different crystalline forms have different X-ray diffraction patterns, infrared spectra, and/or may vary in some or all of the properties, such as melting point, density, hardness, crystal shape, optical properties, electrical properties, stability, solubility, bioavailability, and the like. Recrystallization solvent, crystallization rate, storage temperature, and other factors may cause one form to dominate a given preparation. Various polymorphs of a compound can generally be prepared by crystallization under different conditions.
The term "eutectic" refers to a crystal structure composed of at least two components. In certain embodiments, the co-crystal comprises a compound of interest (e.g., one disclosed herein) and one or more other components, such as, for example, one or more atoms, ions, or molecules (e.g., solvent molecules). In certain embodiments, the co-crystal comprises the target compound and one or more solvent molecules. In certain embodiments, the co-crystal contains the target compound and one or more acids or bases.
The term "prodrug" refers to the form of an active compound that contains one or more cleavable groups that are removed by solvolysis or under physiological conditions to release the active compound. Exemplary prodrug forms include, but are not limited to, choline ester derivatives and the like, as well as N-alkyl morpholinyl esters and the like. In some embodiments, prodrugs can be acid derivatives, such as, for example, esters prepared by reaction of the parent acid compound with a suitable alcohol, amides made by reaction of the parent acid compound with a substituted or unsubstituted amine, anhydrides, or mixed anhydrides, as known in the art. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant to the target compound are specific examples of prodrug forms. In some cases, it is desirable to prepare a diester-type prodrug, such as an (acyloxy) alkyl ester or an ((alkoxycarbonyl) oxy) alkyl ester of the target compound. C of the target Compound1-C8Alkyl radical, C2-C8Alkenyl radical, C2-C8Alkynyl, aryl, C7-C12Substituted aryl, and C7-C12An aralkyl ester.
A "subject" to which administration is contemplated includes, but is not limited to, a human (i.e., a male or female of any age group, such as a pediatric subject (e.g., an infant, a child, an adolescent) or an adult subject (e.g., a young adult, a middle aged adult or an elderly adult), and/or a non-human animal, such as a mammal (e.g., a primate (e.g., a cynomolgus monkey, a rhesus monkey), a domestic animal, such as a cow, a pig, a horse, a sheep, a goat, a cat, and/or a dog, and/or a bird (e.g., a chicken, a duck, a goose, and/or a turkey). For example, subjects who have recently undergone tumor resection. A tumor resected subject is a subject undergoing tumor resection less than 72 hours (including, e.g., less than 48 hours, less than 24 hours, less than 12 hours, less than 6 hours, or less) prior to receiving a drug delivery composition or device described herein. In some embodiments, a tumor resected subject is a subject that has undergone tumor resection within less than 48 hours prior to receiving a drug delivery composition or device described herein. In some embodiments, a tumor resected subject is a subject undergoing tumor resection within less than 24 hours prior to receiving a drug delivery composition or device described herein. In some embodiments, a tumor resected subject is a subject undergoing tumor resection within less than 12 hours prior to receiving a drug delivery composition or device described herein.
The term "biological sample" refers to any sample, including tissue samples (e.g., tissue sections and tissue biopsy); a cell sample (e.g., a cell smear (such as a Pap or blood smear) or a cell sample obtained by fibrodissection); whole organism samples (such as yeast or bacterial samples); or a cellular fraction, fragment or organelle (e.g., obtained by lysing the cell and separating its components by centrifugation or other means). Other examples of biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsy tissue (e.g., obtained by surgical biopsy or needle biopsy), nipple aspirate, milk, vaginal secretion, saliva, a swab (e.g., a buccal swab), or any material comprising a biomolecule derived from a first biological sample.
The term "administration or administration" refers to implanting, absorbing, ingesting, injecting, inhaling or otherwise introducing a drug delivery composition as described herein.
The terms "treat," "treating," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a "pathological condition" (e.g., a disease, disorder, or condition, including one or more signs or symptoms thereof). In some embodiments, the treatment may be administered after one or more signs or symptoms have been developed or observed. Treatment may also be continued after resolution of symptoms, e.g., to delay or prevent relapse and/or spread.
The terms "disorder," "disease," and "condition" are used interchangeably.
An "effective amount" is an amount sufficient to induce a desired biological response (e.g., to treat a disorder in a patient). As will be appreciated by those skilled in the art, an effective amount of a drug delivery composition may vary depending on factors such as: the desired biological endpoint, the pharmacokinetics of the therapeutic agent in the composition, the disorder being treated, and the age and health of the subject. An effective amount encompasses both therapeutic and prophylactic treatment. For example, in treating cancer, an effective amount can prevent tumor regrowth, reduce tumor burden, or stop tumor growth or spread. One skilled in the art will appreciate that an effective amount need not be contained in a single dosage form. Rather, administration of an effective amount can involve potentially administering multiple doses over time (e.g., according to a dosing regimen).
A "therapeutically effective amount" is an amount sufficient to provide a therapeutic benefit in the treatment of a disorder, which therapeutic benefit may be or include, for example, reducing the frequency and/or severity, and/or delaying the onset of one or more characteristics or symptoms associated with the disorder. A therapeutically effective amount means an amount of a therapeutic agent alone or in combination with other therapies that provides a therapeutic benefit in the treatment of a disorder. The term "therapeutically effective amount" can encompass an amount that improves overall treatment, reduces or avoids symptoms or causes of the disorder, or enhances the therapeutic efficacy of another therapeutic agent. One skilled in the art will appreciate that a therapeutically effective amount need not be contained in a single dosage form. Rather, administration of an effective amount can involve potentially administering multiple doses over time (e.g., according to a dosing regimen).
A "prophylactically effective amount" is an amount sufficient to prevent a disorder (e.g., significantly delay the onset or recurrence of one or more symptoms or features of a disorder, e.g., such that the symptom or feature is not detected at a time point when the amount is not administered). A prophylactically effective amount of a composition refers to the amount of a therapeutic agent, alone or in combination with other drugs, that provides a prophylactic benefit in preventing a disorder. The term "prophylactically effective amount" can include an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. One skilled in the art will appreciate that a prophylactically effective amount need not be contained in a single dosage form. Rather, administration of an effective amount can involve potentially administering multiple doses over time (e.g., according to a dosing regimen).
"proliferative disease" refers to a disease that occurs as a result of abnormal growth or multiplication of cells (Walker, Cambridge dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990). Proliferative diseases may be associated with: 1) pathological proliferation of normal resting cells; 2) pathological migration of cells from their normal location (e.g., metastasis of tumor cells); 3) pathological expression of proteolytic enzymes such as matrix metalloproteinases (e.g., collagenase, gelatinase, and elastase); or 4) pathological angiogenesis, such as proliferative retinopathy and tumor metastasis. Exemplary proliferative diseases include cancer (i.e., "malignant neoplasms"), benign neoplasms, angiogenesis or diseases associated with angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases.
The terms "neoplasm" and "tumor" are used interchangeably herein and refer to a mass of abnormal tissue in which the mass grows beyond and is not in proportion to normal tissue. A neoplasm or tumor can be "benign" or "malignant," depending on the following characteristics: degree of cell differentiation (including morphology and function), growth rate, local invasion, and metastasis. A "benign neoplasm" is generally well differentiated, has a growth rate that is characteristically slower than that of a malignant neoplasm, and remains localized to the source site. Furthermore, benign neoplasms do not have the ability to infiltrate, invade, or migrate to a distal site. Exemplary benign neoplasms include, but are not limited to, lipoma, chondroma, adenoma, acrochordon, senile hemangioma, seborrheic keratosis, freckles, and sebaceous hyperplasia. In some cases, certain "benign" tumors can later cause malignant neoplasms, which can be attributed to other genetic changes in the neoplastic cell subpopulation of the tumor, which are referred to as "pre-malignant neoplasms. An example of a pre-malignant neoplasm is a teratoma. In contrast, "malignant neoplasms" are generally poorly differentiated (dysplasia) and have a characteristic rapid growth, with infiltration, invasion and destruction of surrounding tissues. In addition, malignant neoplasms often have the ability to metastasize to distal sites.
The term "metastasis" refers to the spread or migration of cancer cells from a primary or initial tumor to another organ or tissue, which is typically identified by the presence of a "secondary tumor" or "secondary cell mass" of the tissue type of the primary or initial tumor, but not of the organ or tissue type in which the secondary (metastatic) tumor is located. For example, prostate cancer that metastasizes to bone is referred to as metastatic prostate cancer and includes cancerous prostate cancer cells that grow in bone tissue.
The term "cancer" refers to malignant neoplasms (Stedman's Medical Dictionary, 25th ed.; Hensylated.; Williams)&Wilkins: philiadelphia, 1990). Of particular interest in the context of some embodiments of the present disclosure are cancers that are treated by cell killing and/or removal therapies (e.g., surgical resection and/or certain chemotherapeutic therapies such as cytotoxic therapies, etc.). In some embodiments, the cancer treated according to the present disclosure is a cancer that has been surgically resected (i.e., at least one tumor has been surgically resected). In some embodiments, the cancer treated according to the present disclosure is a cancer resected to its standard treatment. In some embodiments, the cancer treated according to the present disclosure is a metastatic cancer. In some embodiments of the present invention, the substrate is, Exemplary cancers may comprise one or more of the following: exemplary cancers include acoustic neuroma; adenocarcinoma; adrenal cancer; anal cancer; angiosarcomas (e.g., lymphangiosarcoma, lymphediosarcoma, angiosarcoma); appendiceal carcinoma; benign monoclonal gammaglobulin; biliary cancer (e.g., cholangiocarcinoma); biliary tract cancer; bladder cancer; bone cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, breast cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastoma, glioma (e.g., astrocytoma, oligodendroglioma), neural tube blastoma); bronchial cancer; carcinoid tumors; a cardiac tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial cancer; ductal carcinoma in situ; ependymoma; endothelial sarcomas (e.g., Kaposi's sarcomas, multiple idiopathic hemorrhagic sarcomas); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett's adenocarinoma); ewing's sarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma); familial hypereosinophilia; gallbladder cancer; stomach cancer (e.g., gastric adenocarcinoma); gastrointestinal stromal tumors (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic cancers (e.g., leukemias, such as Acute Lymphocytic Leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), Acute Myelogenous Leukemia (AML) (e.g., B-cell AML, T-cell AML), Chronic Myelogenous Leukemia (CML) (e.g., B-cell CML, T-cell CML), and Chronic Lymphocytic Leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphomas, such as Hodgkin's Lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-hodgkin's lymphoma (NHL) (e.g., B-cell NHL, such as Diffuse Large Cell Lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), Mantle Cell Lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma) Tumors, nodestral zone B cell lymphomas, splenic marginal zone B cell lymphomas), primary mediastinal B cell lymphomas, burkitt's lymphomas, lymphoplasmacytomas (i.e., waldenstrom's macroglobulinemia: (a)
The term "immunotherapy" refers to a therapeutic agent that facilitates the treatment of a disease by inducing, enhancing or suppressing an immune response. Immunotherapy designed to induce or amplify an immune response is classified as activated immunotherapy, while immunotherapy that reduces or suppresses an immune response is classified as suppressed immunotherapy. Immunotherapy is typically, but not always, a biotherapeutic agent. Many immunotherapies are used to treat cancer. These include, but are not limited to, monoclonal antibodies, adaptive cell transfer, cytokines, chemokines, vaccines, small molecule inhibitors, and small molecule agonists. For example, useful immunotherapies may include, but are not limited to, type I interferon inducers, interferons, interferon gene Stimulator (STING) agonists, TLR7/8 agonists, IL-15 superagonists, anti-PD-1 antibodies, anti-CD 137 antibodies, and anti-CTLA-4 antibodies.
The terms "biologic," "biologic," and "biologic" refer to a variety of products such as vaccines, blood and blood components, allergen preparations, somatic cells, gene therapy, tissues, nucleic acids, and proteins. Biologies may contain sugars, proteins, or nucleic acids, or complex combinations of these, or may be entities such as cells and tissues. Biologies can be isolated from a variety of natural sources (e.g., human, animal, microbial) and/or can be prepared by biotechnological methods and/or other techniques.
The term "antibody" refers to a functional component of serum and is generally referred to as a collection of molecules (antibodies or immunoglobulins) or a molecule (antibody molecule or immunoglobulin molecule). Antibodies are capable of binding to or reacting with specific antigenic determinants (antigens or epitopes) which in turn can lead to the induction of immune effector mechanisms. A single antibody is generally considered monospecific, and the composition of the antibody may be monoclonal (i.e., composed of the same antibody molecule) or polyclonal (i.e., composed of two or more different antibodies reactive with the same or different epitopes on the same antigen or even on distinctly different antigens). Each antibody has a unique structure that allows it to specifically bind its corresponding antigen, and all natural antibodies have the same overall basic structure of two identical light chains and two identical heavy chains. Antibodies are also collectively referred to as immunoglobulins. The antibody may be of human or non-human (e.g., rodent such as murine, dog, camel, etc.) origin (e.g., may have sequences that originally developed in a human or non-human cell or organism), or may be or include a chimeric, humanized, engineered, or rearranged antibody based on, for example, such a human or non-human antibody (or, in some embodiments, on an antigen-binding portion thereof).
In some embodiments, as is apparent from the context, the term "antibody" as used herein encompasses forms comprising an epitope-binding sequence of an antibody, such forms including, for example, chimeric and/or single chain antibodies (e.g., nanobodies or Fcab), as well as antibody binding fragments, such as Fab, Fv fragments or single chain Fv (scFv) fragments, and multimeric forms, such as dimeric IgA molecules or pentavalent IgM molecules. Also comprisesBispecific antibodies, bispecific T cell conjugates (BiTEs), immortal monoclonal T cell receptors against cancer (ImmTACs), Dual Affinity Relocation (DART); alternative scaffolds or antibody mimics (e.g., anti-transporter, FN3 monoclonal antibodies, DARPins, Affibodies, Affilins, Affimers, Affitins, Α bodies, Avimers, Fynomers, Im7, VLR, VNAR, Trimab, CrossMab, Trident); nanobodies, double Nanobodies, F (ab')2Fab', di-sdFv, single domain antibodies, trifunctional antibodies, diabodies, and mini antibodies.
The term "small molecule" or "small molecule therapeutic agent" refers to a naturally occurring or artificially created (e.g., by chemical synthesis) molecule having a relatively low molecular weight. Typically, the small molecule is an organic compound (i.e., it contains carbon). Small molecules may contain multiple carbon-carbon bonds, stereocenters, and other functional groups (e.g., amines, hydroxyls, carbonyls, and heterocycles, etc.). In certain embodiments, the small molecule has a molecular weight of no greater than about 1,000g/mol, no greater than about 900g/mol, no greater than about 800g/mol, no greater than about 700g/mol, no greater than about 600g/mol, no greater than about 500g/mol, no greater than about 400g/mol, no greater than about 300g/mol, no greater than about 200g/mol, or no greater than about 100 g/mol. In certain embodiments, the small molecule has a molecular weight of at least about 100g/mol, at least about 200g/mol, at least about 300g/mol, at least about 400g/mol, at least about 500g/mol, at least about 600g/mol, at least about 700g/mol, at least about 800g/mol, or at least about 900g/mol, or at least about 1,000 g/mol. Combinations of the above ranges (e.g., at least about 200g/mol and not greater than about 500g/mol) are also possible. In certain embodiments, the small molecule is a therapeutically active agent such as a drug (e.g., a molecule approved by the U.S. food and drug administration according to the regulations of federal regulations (c.f.r.). Small molecules may also coordinate to one or more metal atoms and/or metal ions. In this case, the small molecule is also referred to as a "small organometallic molecule". Preferred small molecules are biologically active because they produce a biological effect in an animal, preferably a mammal, more preferably a human. Small molecules include, but are not limited to, radionuclides and imaging agents. In certain embodiments, the small molecule is a drug. Preferably, although not necessarily, the medicaments are those that have been deemed safe and effective for use in humans or animals by a suitable governmental or regulatory agency. For example, approved human drugs listed by the FDA under 21C.F.R. § 330.5, 331-361, and 440-460; veterinary drugs listed by FDA under 21c.f.r. § 500-589, which are incorporated herein by reference. According to the present invention, all listed drugs are considered acceptable for use.
The term "therapeutic agent" refers to an agent having one or more therapeutic properties that produce a desired, usually beneficial, effect. For example, a therapeutic agent can treat, ameliorate, and/or prevent a disease. The therapeutic agent may be or include a biological agent, a small molecule, or a combination thereof.
The term "chemotherapeutic agent" refers to a therapeutic agent known for cancer chemotherapy.
The term "targeted agent" refers to an anti-cancer drug that prevents the growth and spread of cancer by interfering with specific molecules ("molecular targets") involved in the growth, progression, and spread of cancer. Sometimes referred to as "targeted cancer therapy," molecular targeted drugs, "" molecular targeted therapy, "or" precision drugs. Targeted drugs differ from standard chemotherapy in that targeted drugs act on specific molecular targets associated with cancer, whereas many chemotherapeutic agents act on all rapidly dividing cells (e.g., whether cancer cells or not). Targeted drugs are deliberately selected or designed to interact with their target, but many standard chemotherapies have been identified because they kill cells.
The term "biomaterial" refers to a biocompatible material characterized as being administrable to a subject for medical purposes (e.g., treatment, diagnosis) without eliciting an unacceptable (according to sound medical judgment) response. The biological material may be obtained naturally or synthetically. In some embodiments, the biomaterial may be in the form of a gel. In some embodiments, the biomaterial may be in an injectable form. For example, the biomaterial may include a gel precursor component that will form a gel in situ (e.g., when administered to a subject).
The term "hydrogel" refers to a material formed from a network of hydrophilic polymer chains, sometimes in the form of a colloidal gel in which the aqueous phase is the dispersion medium. In some embodiments, the hydrogel has a natural or synthetic polymer network that is highly absorbent (e.g., it can absorb and/or retain more than 90% of the water). In some embodiments, the hydrogel has a softness similar to natural tissue, for example, due to its significant water content.
The terms "implantable", "implantation" and "implant" refer to the placement of a drug delivery composition at a specific location in a subject, for example within a tumor resection site or within an sentinel lymph node, and typically by general surgical methods.
The term "biocompatible" refers to a material that is substantially non-toxic in the in vivo environment in which it is intended for use, and is substantially not rejected by the patient's physiological system (i.e., is non-antigenic). This can be measured by the ability of the material to pass the biocompatibility test set forth in: international Standards Organization (ISO) Standard 10993 and/or United States Pharmacopeia (USP)23 and/or United states Food and Drug Administration (FDA) blue skin book Memo No. G95-1 entitled "Use of International Standard ISO-10993, Biological Evaluation of medical devices Part-1: Evaluation and Testing". Generally, these tests can measure toxicity, infectivity, pyrogen, irritation potential, reactivity, hemolytic activity, carcinogenicity, and/or immunogenicity of the material. When introducing biocompatible structures or materials into most patients, it will not elicit undesirable adverse, persistent or escalating biological reactions or responses, and is distinguished from mild, transient inflammation, which is often associated with surgery or the implantation of foreign objects into living organisms.
The term "antagonist" refers to the following agents: which (i) reduces or inhibits one or more effects of another agent; and/or (ii) reducing or inhibiting one or more biological events. In some embodiments, an antagonist may decrease the level and/or activity of one or more agents it targets. In various embodiments, antagonists may be or include agents of various chemical classes, including, for example, small molecules, polypeptides, nucleic acids, carbohydrates, lipids, metals, and/or other entities that exhibit relevant antagonist activity. An antagonist may be direct (in which case it exerts an effect directly on its target) or indirect (in which case it does not exert an effect by binding to its target; e.g., by interacting with a modulator of the target thereby causing a change in the level or activity of the target). In some embodiments, the antagonist may be a receptor antagonist, e.g., a receptor ligand or drug that blocks or alleviates a biological response by binding and blocking the receptor rather than activating the receptor as an agonist would.
The term "agonist" refers to an agent that (i) increases or causes one or more effects of another agent; and/or (ii) increase or cause one or more biological events. In some embodiments, an agonist may increase the level and/or activity of one or more agents it targets. In various embodiments, an agonist can be or include an agent of various chemical classes, including, for example, small molecules, compounds, nucleic acids, carbohydrates, lipids, metals, and/or other entities that exhibit relevant agonist activity. An agonist may be direct (in which case it directly affects its target) or indirect (in which case it does not affect by binding to its target; e.g., by interacting with a modulator of the target, e.g., thereby altering the level or activity of the target). A partial agonist may act as a competitive antagonist in the presence of a full agonist, in that it competes with a full agonist for interaction with its target and/or its modulator, thereby resulting in (i) a reduction in one or more effects of another agent, and/or (ii) a reduction in one or more biological events, when compared to that observed with a full agonist alone.
The term "inhibit (inhibition or inhibition)" is not limited to only complete inhibition in the context of modulating target (e.g., p38 MAPK) levels (e.g., expression and/or activity). Thus, in some embodiments, partial inhibition or relative reduction is also encompassed within the term "inhibiting". In some embodiments, the term refers to a reduction in the level (e.g., expression, and/or activity) of a target (e.g., p38 MAPK) to a level that is reproducibly and/or significantly lower than the initial level or other suitable reference level (which may, for example, be a baseline level for the target). In some embodiments, the term refers to a decrease in the level (e.g., expression and/or activity) of a target to a level that: less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of the initial level (which may be, for example, the baseline level of the target).
As used herein, the term "inhibitor" refers to an agent whose presence or level correlates with a decrease in the level or activity of a target to be modulated. In some embodiments, the inhibitor may act directly (in which case it directly affects its target, e.g., by binding to the target); in some embodiments, the inhibitor may act indirectly (in which case it acts by interacting with and/or otherwise altering the modulator of the target, thereby reducing the level and/or activity of the target). In some embodiments, an inhibitor is a substance whose presence or level correlates with a target level or activity that is reduced relative to a particular reference level or activity (e.g., observed under suitable reference conditions, such as the presence of a known inhibitor, or the absence of an inhibitor disclosed herein, etc.).
As used herein, the term "proinflammatory pathway inhibitor", in some embodiments, refers to an agent that: it prevents recruitment of immunosuppressive cells or prevents acute inflammation. Such acute inflammation and/or immunosuppressive cell recruitment may occur following local edema (including those resulting from surgery). In some embodiments, the proinflammatory pathway inhibitor can inhibit, e.g., induce an immune response to inflammation, including, e.g., production of proinflammatory cytokines (e.g., TNF- α, IL-1 β, and IL-6), increase activity and/or proliferation of Th1 cells, recruitment of bone marrow cells, and the like.
The term "proinflammatory immune response", as used herein, refers to an immune response that induces inflammation, including, for example, production of proinflammatory cytokines (e.g., TNF- α, IL-1 β, and IL-6), increased activity and/or proliferation of Th1 cells, recruitment of bone marrow cells, and the like. In some embodiments, the proinflammatory immune response can be or include one or both of acute inflammation and chronic inflammation.
The term "innate immune response activator" refers to an agent that activates the innate immune system. Such activation may stimulate the expression of molecules that elicit an inflammatory response and/or contribute to the induction of an adaptive immune response, resulting in the development of antigen-specific acquired immunity. Activation of the innate immune system can lead to cytokine production, proliferation, and survival, and improve T-priming by enhancing antigen presentation and expression of costimulatory molecules by antigen presenting cells.
The term "adaptive immune response activator" refers to an agent that activates the adaptive immune system. Such activation can restore anti-tumor function by: by neutralizing inhibitory immune checkpoints, or by triggering costimulatory receptors, helper and/or effector T cell responses against immunogenic antigens expressed by cancer cells are ultimately generated and memory B cell and/or T cell populations are generated. In certain embodiments, the adaptive immune response activator is involved in modulating the adaptive immune response and/or leukocyte trafficking.
The term "modulator of macrophage effector function" refers to an agent that activates macrophage effector function or depletes immunosuppressive macrophages or suppressor cells derived from macrophages. Such enhancement may immobilize macrophage and bone marrow components to destroy tumors and their stroma, including tumor vasculature. Macrophages can be induced to secrete anti-tumor cytokines and/or to exert phagocytosis, including antibody-dependent cellular phagocytosis.
As used herein, the terms "sustained release" and "extended release" are equivalent terms. The compositions and devices of the present disclosure may release the therapeutic agent over a period of time. The terms "sustained" and "prolonged" may refer to the release of one or more therapeutic agents from a biological material over a time scale of 5 minutes to several months. In certain embodiments, less than or equal to 90%, less than or equal to 80%, less than or equal to 70%, less than or equal to 60%, less than or equal to 50%, less than or equal to 40%, less than or equal to 30%, less than or equal to 20%, less than or equal to 10%, less than or equal to 5%, or less than or equal to 1% of the one or more therapeutic agents are released from the biological material over the following period of time: 4 weeks, 3 weeks, 2 weeks, 10 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, 18 hours, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, 15 minutes, 10 minutes, or 5 minutes. In certain embodiments, greater than or equal to 99%, greater than or equal to 95%, greater than or equal to 90%, greater than or equal to 80%, greater than or equal to 70%, greater than or equal to 60%, greater than or equal to 50%, greater than or equal to 40%, greater than or equal to 30%, greater than or equal to 20%, greater than or equal to 10%, greater than or equal to 5%, or greater than or equal to 1% of one or more of the following is released from the biological material over a period of time: 1 day, 18 hours, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, 15 minutes, 10 minutes, or 5 minutes. In some embodiments, the extent of sustained or extended release can be characterized in vitro or in vivo. For example, in some embodiments, release kinetics can be tested in vitro by placing a composition comprising a biomaterial and a therapeutic agent (e.g., a p38 MAPK inhibitor) in an aqueous buffered solution (e.g., PBS, pH 7.4). In some embodiments, when a composition comprising a biomaterial and a therapeutic agent (e.g., a p38 MAPK inhibitor) is placed in an aqueous buffered solution (e.g., PBS, pH 7.4), less than 100% or less (including, e.g., less than or equal to 90%, less than or equal to 80%, less than or equal to 70%, less than or equal to 50% or less) of the therapeutic agent is released from the biomaterial within 3 hours. In some embodiments, release kinetics can be tested in vivo by implanting a composition comprising a biomaterial and a therapeutic agent (e.g., a p38 MAPK inhibitor) into a target site (e.g., a milk fat pad) of an animal subject (e.g., a mouse subject). In some embodiments, when a composition comprising a biomaterial and a therapeutic agent (e.g., a p38 MAPK inhibitor) is implanted into a target site (e.g., a milk fat pad) of an animal subject (e.g., a mouse subject), less than or equal to 70% or less (including, e.g., less than or equal to 60%, less than or equal to 50%, less than 40%, less than 30% or less) of the therapeutic agent is released in vivo 8 hours after implantation.
Drawings
Figure 1 is a Kaplan-Meier curve of female BALB/cJ mice inoculated in situ with 4T1-Luc2 cells, whose tumors were surgically excised and then implanted with an exemplary drug delivery device comprising a hydrogel (e.g., a cross-linked hyaluronic acid hydrogel) but without a p38 MAPK inhibitor or an exemplary drug delivery device comprising a hydrogel (e.g., cross-linked hyaluronic acid) and a p38 MAP kinase inhibitor (e.g., loshapimod).
Fig. 2 is a Kaplan-Meier curve of female BALB/cJ mice inoculated in situ with 4T1-Luc2 cells, whose tumors were surgically excised and then implanted with an exemplary drug delivery device comprising a hydrogel (e.g., a cross-linked hyaluronic acid hydrogel) but no anti-IL-1 β antibody or an exemplary drug delivery device comprising a hydrogel (e.g., cross-linked hyaluronic acid) and an anti-IL-1 β antibody (e.g., clone B122).
FIG. 3 is a Kaplan-Meier curve of female BALB/cJ mice inoculated in situ with 4T1-Luc2 cells, whose tumors were surgically excised and then implanted with an exemplary drug delivery device comprising a hydrogel (e.g., cross-linked hyaluronic acid hydrogel) but no anti-IL-6 antibody or an exemplary drug delivery device comprising a hydrogel (e.g., cross-linked hyaluronic acid) and an anti-IL-6 antibody (e.g., clone MP5-20F 3).
FIG. 4 is a schematic diagram showing the interrelationship of certain pro-inflammatory pathways involving p38 mitogen-activated protein kinase (MAPK) and COX-2. See Desai et al, "Mechanisms of Phytoprint Modulation of Cycloaxagenase-2 (COX-2) and Inflammation Related to Cancer" Nutrition and Cancer, "70: 350-375 (2018). Those skilled in the art familiar with such pathways will appreciate that pro-inflammatory signals, such as, for example, the cytokines TNF- α, IL-6 and/or IL-1 β, may stimulate COX-2 transcription by, for example, activating the MAPK pathway. For example, IL-1 β has been shown to upregulate COX-2expression by activating the p38 MAPK pathway (Huang et al, "MAPK/ERK signaling pathway involved expressed expression of COX-2and VEGF by IL-1beta induced in human endometeriometry storage cells in vitro," Int J Clin Exp Pathol,6:2129-2136(2013), Di Mari et al, "HETES enhanced IL-1-mediated COX-2expression vision evaluation of message status in human collagen bacteria of disorders," Am J Physiol-Gastroitopter physiology, 293: 2-2101 (2007)).
Figure 5 is a schematic (NSAID) showing certain non-steroidal anti-inflammatory drugs that may be used as Cyclooxygenase (COX) inhibitors, including for example COX-1 inhibitors and/or COX-2 inhibitors, and/or p38 MAPK inhibitors. See Esposito et al, "Non-stereo anti-reflective drugs in Parkinson's disease" Experimental Neurology 205:295-312 (2007). For example, in some embodiments, the NSAID may inhibit or reduce the activity and/or level of COX-1 and/or COX-2. In some embodiments, the NSAID may inhibit or reduce activation of the p38 MAPK pathway or a component thereof, thereby reducing or inhibiting AP-1 activation.
FIG. 6 is a schematic representation of the interrelationship of certain pro-inflammatory pathways involving p38 mitogen-activated protein kinase (MAPK) and Wnt- β -catenin. See Bikkavilli et al, "p 38 mitogen-activated protein kinase ligands Wnt-beta-catenin signaling by activation of GSK3 beta" journal of Cell Science,121:3598-3607 (2008). Those skilled in the art familiar with such pathways will appreciate that p38MAPK can be activated by Wnt3a stimulation, and that such stimulation can be dependent on both G-proteins and dishevelles. p38MAPK specific inhibitors may reduce Wnt3 a-induced β -catenin expression. Thus, p38MAPK plays a role in Wnt- β -catenin signaling, for example, by inactivating GSK3 β and/or by manipulation downstream of disheveleds.
Detailed Description
Provided herein are drug delivery compositions and devices that can target the delivery of one or more immunomodulatory agents to a target site (e.g., a site where a tumor has been removed and/or cancer cells have been treated or killed (e.g., by chemotherapy or radiation)) thereby focusing the effect of the immunomodulatory agents to the target site in need thereof. Such drug delivery systems are particularly useful for treating cancer. Drug delivery compositions and devices can comprise a biomaterial and a proinflammatory pathway inhibitor. In some aspects, drug delivery compositions and devices can comprise a biomaterial and an inhibitor of a pro-inflammatory immune response mediated by a p38 mitogen-activated protein kinase (MAPK) pathway (e.g., a p38MAPK inhibitor). Drug delivery compositions and devices may comprise a biomaterial, an inhibitor of a pro-inflammatory immune response mediated by the p38 mitogen-activated protein kinase (MAPK) pathway, and an innate immune response activator. Drug delivery compositions and devices may comprise biomaterials, inhibitors of pro-inflammatory immune responses mediated by the p38 mitogen-activated protein kinase (MAPK) pathway, activators of innate immune responses, and cytokines. Drug delivery compositions and devices may comprise biomaterials, inhibitors of pro-inflammatory immune responses mediated by the p38 mitogen-activated protein kinase (MAPK) pathway, activators of innate immune responses, and chemokines. The drug delivery compositions and devices may further comprise one or more adaptive immune response activators. The drug delivery compositions and devices may further comprise other therapeutic agents (e.g., pro-inflammatory pathway inhibitors, macrophage effector function modulators, or chemotherapeutic agents).
In some embodiments, the therapeutic agents (e.g., immunomodulators) provided in drug delivery compositions and devices can mediate inflammation (e.g., chronic inflammation) induced, for example, by surgery, such as tumor resection surgery, thereby providing a unique tool for treating cancer, particularly solid tumors. In some embodiments, the therapeutic agents (e.g., immunomodulators) provided in the drug delivery compositions and devices can inhibit inflammation (e.g., chronic inflammation) induced, for example, by surgery, such as tumor resection surgery. In some embodiments, the therapeutic agents (e.g., immunomodulators) provided in the drug delivery compositions and devices can reduce or inhibit the activity of myeloid-derived suppressor cells (MDSCs). In some embodiments, therapeutic agents (e.g., immunomodulators) provided in drug delivery compositions and devices can reduce or inhibit immunosuppressive cell recruitment. In some embodiments, the therapeutic agents (e.g., immunomodulators) provided in the drug delivery compositions and devices can reduce or inhibit acute inflammation. In some embodiments, the drug delivery compositions and devices may further comprise one or more therapeutic agents (e.g., immunomodulators) that activate the innate immune response system and/or the adaptive immune response system. The compositions, devices, methods, systems and kits provided herein also have advantages over existing methods in that they do not require administration of cells (e.g., adoptive cell transfer) or the addition or presence of other components (e.g., microparticles, peptides or tumor antigens).
The drug delivery compositions and devices described herein can be used to treat cancer (e.g., solid tumors) perioperatively. In some embodiments, the compositions and devices can deliver immunotherapy by implanting one or more devices at a site in need of treatment in a subject in need of treatment. The drug delivery compositions and devices described herein are particularly advantageous over existing immunotherapies because, in some embodiments, they can release immunomodulatory agents (e.g., p38MAPK inhibitors) directly to the site of tumor resection, thereby avoiding systemic administration. Thus, the drug delivery compositions and devices described herein provide a vehicle for drug delivery at the site of tumor resection that avoids the potential toxicity that may be associated with traditional systemic immunotherapy administration. Focusing immunotherapy on the tumor resection site can similarly improve efficacy. In certain embodiments, the drug delivery compositions and devices can be used to slow and/or arrest tumor growth, prevent cancer recurrence, prevent tumor metastasis, and/or prevent primary tumor regeneration.
Among other things, in some embodiments, the present disclosure provides techniques for suppressing an immune response that itself promotes additional immunosuppression (e.g., activity of MDSCs).
Without wishing to be bound by any particular theory, the present disclosure indicates that, in some embodiments, the techniques provided herein can reduce the type of inflammation typically observed in the case of chronic inflammation (e.g., often associated with autoimmune diseases), but as described herein, can be activated in emergency situations (i.e., post-surgery). The present disclosure provides the following insights: therapy targeting p38 as described herein may be the only useful in the context of post-tumor resection. For example, p38 has been described as being associated with certain autoimmune disorders, and has been targeted in therapies to treat such disorders. Those skilled in the art will appreciate that many therapeutic strategies designed for and/or effective in the treatment of autoimmune diseases will be catastrophic in the case of tumor resection, as they will lead to a worsening of the tumor progression phenotype. Despite this general principle, the present disclosure teaches that targeting p38 as described herein is surprisingly useful in the treatment of cancer.
In some embodiments, the described therapies targeting p38 may be combined, for example, with therapies that include other immune modulation strategies, e.g., to activate/agonize the innate immune system (e.g., by administering agents such as STING agonists or TLR agonists).
Drug delivery compositions and devices
Biomaterials (e.g., hydrogels)
Drug delivery compositions and devices include biomaterials. In certain embodiments, the biomaterial is a scaffold or reservoir. The stent or reservoir comprises any synthetic or natural material suitable for inclusion in the drug delivery compositions and devices described herein and comprising any therapeutic agent and any agent therein that facilitates sustained or extended release. Thus, the biomaterial has properties (e.g., storage modulus, biodegradation, therapeutic agent release profile) that provide the advantageous properties of the compositions and devices described herein.
In certain embodiments, the biomaterial prolongs the release of the therapeutic agent at the tumor resection site relative to the same therapeutic agent administered in solution. In certain embodiments, the biomaterial extends the release of the therapeutic agent at the tumor resection site by at least 5 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 18 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, or 4 weeks relative to the same therapeutic agent administered in solution.
In some embodiments, the biomaterial prolongs the release of the therapeutic agent (e.g., a p38 MAPK inhibitor), and thus, when evaluated at a specific time point after administration, there is more therapeutic agent present at the site of tumor resection than is observed when the therapeutic agent is administered in solution. For example, in some embodiments, the amount of therapeutic agent released to and present at the tumor resection site is at least 30% greater (including, e.g., at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or more) than the amount observed when the therapeutic agent is administered in solution, when assessed 24 hours after administration. In some embodiments, the amount of therapeutic agent released to and present at the tumor resection site is at least 30% more (including, e.g., at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or more) than the amount observed when the therapeutic agent is administered in solution, when assessed 48 hours after administration. In some embodiments, the amount of therapeutic agent released to and present at the tumor resection site is at least 30% more (including, e.g., at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or more) than the amount observed when the therapeutic agent is administered in solution, when evaluated 3 days after administration. In some embodiments, the amount of therapeutic agent released to and present at the tumor resection site is at least 30% more (including, e.g., at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or more) than the amount observed when the therapeutic agent is administered in solution, when evaluated 5 days after administration.
In some embodiments, the biomaterial is characterized by a storage modulus as follows: at least 500Pa, at least 1000Pa, at least 1500Pa, at least 2000Pa, at least 2500Pa, at least 3000Pa, at least 4000Pa, at least 5000Pa, at least 10kPa, at least 15kPa, or higher. In some embodiments, the biomaterial is characterized by a storage modulus as follows: not more than 50kPa, not more than 40kPa, not more than 30kPa, not more than 20kPa, not more than 10kPa, not more than 5000kPa, not more than 4000Pa, not more than 3000Pa, not more than 2000Pa, or lower. Combinations of the above ranges are also possible. For example, in some embodiments, the biomaterial is characterized by a storage modulus as follows: from 500Pa to 50,000Pa, or from 1000Pa to 20kPa, or from 1000Pa to 10kPa, or from 1000Pa to 5000Pa, or from 1000Pa to 3000 Pa.
In certain embodiments, the biomaterial comprises hyaluronic acid, alginate, chitosan, chitin, chondroitin sulfate, dextran, gelatin, collagen, starch, cellulose, polysaccharide, fibrin, ethylene-vinyl acetate (EVA), poly (lactic-co-glycolic acid) (PLGA), polylactic acid (PLA), polyglycolic acid (PGA), polyethylene glycol (PEG), PEG diacrylate (PEGDA), disulfide-containing PEGDA (pegsda), PEG dimethacrylate (PEGDMA), Polydioxanone (PDO), Polyhydroxybutyrate (PHB), poly (2-hydroxyethyl methacrylate) (pHEMA), Polycaprolactone (PCL), poly (beta-amino ester) (PBAE), poly (ester amide), poly (propylene glycol) (PPG), poly (aspartic acid), poly (glutamic acid), poly (propylene glycol fumarate) (PPF), poly (sebacic anhydride) (PSA), poly (propylene carbonate) (PTMC), poly (desaminotyrosyl tyrosine alkyl ester carbonate) (PDTE), poly [ bis (trifluoroethoxy) phosphazene ], polyoxymethylene, single-walled carbon nanotubes, polyphosphazene, polyanhydride, poly (N-vinyl-2-pyrrolidone) (PVP), poly (vinyl alcohol) (PVA), poly (acrylic acid) (PAA), poly (methacrylic acid) (PMA), polyacetals, poly (alpha esters), poly (ortho esters), polyphosphates, polyurethanes, polycarbonates, polyamides, polyhydroxyalkanoates, polyglycerol, polyglucuronic acid, derivatives thereof, and/or combinations thereof.
In certain embodiments, the biomaterial is or comprises a non-crosslinked biomaterial. In certain embodiments, the biomaterial is or comprises a crosslinked biomaterial. For example, in some embodiments, such crosslinked biomaterials are or comprise hydrogels. The hydrogel may be crosslinked using any method known in the art. One skilled in the art will appreciate that in some cases, the hydrogel may be crosslinked, for example, using the following method: chemical crosslinking methods (e.g., by using small molecule crosslinkers, which may be derived from natural sources or synthetic), polyelectrolyte crosslinking (e.g., mixing a polymer with a polymer comprising opposite charges), thermally-induced crosslinking, photo-induced crosslinking (e.g., using vinyl sulfone, methacrylic acid)Esters, acrylic acid), pH-induced crosslinking, and/or enzyme-catalyzed crosslinking. In some embodiments, Parhi, Adv Pharm bull, Review 7 (4): 515-530(2017) may be used to form a hydrogel. In some embodiments, the hydrogel can be crosslinked by attaching: a thiol (for example,) Methacrylate, hexadecane amide (e.g., ) And/or tyramine (e.g.,
In some embodiments, the hydrogel biomaterial is characterized by a storage modulus as follows: at least 500Pa, at least 1000Pa, at least 1500Pa, at least 2000Pa, at least 2500Pa, at least 3000Pa, at least 4000Pa, at least 5000Pa, at least 10kPa, at least 15kPa, at least 20kPa, at least 25kPa, at least 30kPa, at least 35kPa, at least 40kPa, or higher. In some embodiments, the hydrogel biomaterial is characterized by a storage modulus as follows: not more than 50kPa, not more than 40kPa, not more than 30kPa, not more than 20kPa, not more than 10kPa, not more than 5000Pa, not more than 4000Pa, not more than 3000Pa, not more than 2000Pa, or lower. Combinations of the above ranges are also possible. For example, in some embodiments, the hydrogel biomaterial is characterized by a storage modulus as follows: from 500Pa to 50kPa, or from 1000Pa to 20kPa, or from 1000Pa to 10kPa, or from 500Pa to 5000Pa, or from 500Pa to 3000 Pa. In some embodiments, the storage modulus of a hydrogel biomaterial can be determined when it is fully saturated with an aqueous solution (e.g., water).
In some embodiments, the biomaterial (e.g., hydrogel biomaterial) is characterized by a viscosity (e.g., shear rate of 1000s measured at 10 ℃)-1): at least 5mPa/s, at least 10mPa/s, at least 20mPa/s, at least 30mPa/s, at least 40mPa/s, at least 50mPa/s, or higher. In some embodiments, the hydrogel biomaterial is characterized by a viscosity (e.g., shear rate of 1000s, measured at 10 ℃)-1): not more than 50mPa/s, not more than 45mPa/s, not more than 40mPa/s, not more than 35mPa/s, not more than 30mPa/s, not more than 25mPa/s, not more than 20mPa/s, not more than 15mPa/s, not more than 10mPa/s, or lower. Combinations of the above ranges are also possible. For example, in some embodiments, the hydrogel biomaterial is characterized by a viscosity (e.g., shear rate of 1000s, measured at 10 ℃)-1): 5-50mPa/s, or 10-40mPa/s, or 20-30 mPa/s. In some embodiments, the viscosity of the hydrogel biomaterial can be measured using a rheometer.
In certain embodiments, the biomaterial (e.g., hydrogel biomaterial) is or includes hyaluronic acid, alginate, chitosan, chondroitin sulfate, dextran, gelatin, collagen, starch, cellulose, polysaccharide, fibrin, polyethylene glycol (PEG), PEG diacrylate
(PEGDA), disulfide bond-containing PEGDA (PEGSSDA), PEG dimethacrylate (PEGDMA), poly (2-hydroxyethyl methacrylate) (pHEMA), poly (. beta. -amino ester) (PBAE), poly (aspartic acid), poly (glutamic acid), poly (propylene glycol)
(PPG), poly (vinyl alcohol) (PVA), polyacetals, polyglycerols, polyglucuronic acid, or combinations thereof. In certain embodiments, when the biomaterial is a hydrogel, then the therapeutic agent of the composition or device is a hydrophilic molecule. In certain embodiments, when the biomaterial is a hydrogel, then the therapeutic agent of the composition or device is a hydrophobic molecule. In certain embodiments, when the biomaterial is a hydrogel, then the therapeutic agent of the composition or device is a hydrophobic or hydrophilic molecule. In certain embodiments, when the biomaterial is a hydrogel, then the therapeutic agent of the composition or device is a hydrophobic and hydrophilic molecule.
In certain embodiments, the biomaterial is hyaluronic acid or alginate. In certain embodiments, the biomaterial is cross-linked hyaluronic acid or cross-linked alginate. In certain embodiments, the biomaterial comprises hyaluronic acid or alginate. In certain embodiments, the biomaterial comprises cross-linked hyaluronic acid or cross-linked alginate. In certain embodiments, the hydrogel is hyaluronic acid or alginate. In certain embodiments, the hydrogel is cross-linked hyaluronic acid or cross-linked alginate. In certain embodiments, the hydrogel comprises hyaluronic acid or alginate. In certain embodiments, the hydrogel comprises cross-linked hyaluronic acid or cross-linked alginate.
In certain embodiments, the biomaterial comprises hyaluronic acid. In certain embodiments, the biomaterial comprises cross-linked hyaluronic acid. In certain embodiments, the biomaterial is hyaluronic acid. In certain embodiments, the biomaterial is cross-linked hyaluronic acid. In certain embodiments, the hydrogel comprises hyaluronic acid. In certain embodiments, the hydrogel comprises cross-linked hyaluronic acid. In certain embodiments, the hydrogel is hyaluronic acid. In certain embodiments, the hydrogel is a crosslinked hyaluronic acid.
Hyaluronic acid, also known as hyaluronic acid, is an anionic, non-sulfated mucopolysaccharide that is widely distributed throughout connective, epithelial and neural tissue. It is unique among mucopolysaccharides because it is non-sulfated, forms in the plasma membrane rather than in the golgi apparatus, and can be very large, typically reaching millions of molecular weights.
Hyaluronic acid is one of the major components of the extracellular matrix, and plays an important role in cancer metastasis because it contributes significantly to cell proliferation and migration. In certain cancers, hyaluronic acid levels are associated with malignancy and poor prognosis. Hyaluronic acid is commonly used as a tumor marker for certain cancers (e.g., prostate and breast cancer), and may also be used to monitor the progression of the disease in an individual. Thus, the use of hyaluronic acid as a biomaterial in the disclosed drug delivery compositions and devices provides an unexpectedly useful and effective cancer treatment.
In certain embodiments, hyaluronic acid may be crosslinked by attaching: a thiol (for example,
In certain embodiments, the hyaluronic acid comprises a thiol-modified hyaluronic acid and a cross-linking agent. In certain embodiments, the hydrogel comprises a thiol-modified hyaluronic acid (e.g.,) And thiol-reactive PEGDA cross-linkers (e.g.,). In certain embodiments, the thiol-modified hyaluronic acid and thiol-reactive PEGDA crosslinker are combined to form a crosslinked hydrogel that can be used in the drug delivery compositions and devices described herein.
In certain embodiments, the amount and concentration of the thiol-modified hyaluronic acid, the thiol-reactive hyaluronic acid, and the cross-linking agent may be adjusted to provide drug delivery compositions and devices having desirable physical properties (e.g., having a storage modulus of about 500Pa to about 3000 Pa).
In certain embodiments, the biomaterial comprises alginate. In certain embodiments, the biomaterial comprises cross-linked alginate. In certain embodiments, the biomaterial is alginate. In certain embodiments, the biomaterial is a cross-linked alginate. In certain embodiments, the hydrogel comprises alginate. In certain embodiments, the hydrogel comprises cross-linked alginate. In certain embodiments, the hydrogel is alginate. In certain embodiments, the hydrogel is a cross-linked alginate. In certain embodiments, the biomaterial does not comprise alginate. In certain embodiments, the biomaterial is not alginate. In certain embodiments, the hydrogel is not alginate. In certain embodiments, the hydrogel does not comprise alginate.
In certain embodiments, the alginate may be ionically crosslinked by the addition of a salt (e.g., calcium chloride) that promotes crosslinking.
In certain embodiments, the alginate comprises alginate and a cross-linking agent (e.g., calcium chloride). In certain embodiments, the hydrogel comprises alginate and a crosslinking agent (e.g., calcium chloride). In certain embodiments, the alginate and calcium chloride (e.g., ionic cross-linking agents) are combined to form a cross-linked hydrogel that can be used in the drug delivery compositions and devices described herein.
In certain embodiments, the amounts and concentrations of alginate and calcium chloride may be adjusted to provide drug delivery compositions and devices having desirable physical properties, such as having a storage modulus of about 500Pa to about 3000 Pa.
In certain embodiments, the biomaterial is a hydrophobic polymer. In certain embodiments, the hydrophobic polymer is ethylene-vinyl acetate (EVA), poly (lactic-co-glycolic acid) (PLGA), polylactic acid (PLA), polyglycolic acid (PGA), Polydioxanone (PDO), Polyhydroxybutyrate (PHB), Polycaprolactone (PCL), poly (ester amide), poly (propylene glycol fumarate) (PPF), poly (sebacic anhydride) (PSA), poly (propylene carbonate) (PTMC), poly (desaminotyrosyl tyrosine alkyl ester carbonate) (PDTE), poly [ bis (trifluoroethoxy) phosphazene ], polyoxymethylene, single-walled carbon nanotubes, polyphosphazene, polyanhydride, poly (N-vinyl-2-pyrrolidone) (PVP), poly (acrylic acid) (PAA), poly (methacrylic acid) (PMA), poly (alpha ester), poly (orthoester), polyphosphate, a polyurethane, a polycarbonate, a polyamide, or a polyhydroxyalkanoate. The use of hydrophobic polymers as biomaterials may be particularly useful when the therapeutic agent in the composition or device is hydrophilic. The hydrophobic therapeutic agent will be expected to be released over a longer period of time (e.g., days/weeks) than the release time scale (e.g., hours) that is more conducive to imparting a therapeutic effect. Thus, in certain embodiments, when the biomaterial is a hydrophobic polymer, then the therapeutic agent of the composition or device is a hydrophilic molecule.
In certain embodiments, the biomaterial comprises a crosslinked biologic. In certain embodiments, the biologic is crosslinked by self-sacrificing crosslinker disulfide-bis (1H-imidazole-1-carboxylic acid ethyl ester) (DIC). In certain embodiments, the resulting hydrogel is loaded with small molecules.
Proinflammatory pathway inhibitors
The drug delivery compositions and devices can comprise a proinflammatory pathway inhibitor. Drug delivery compositions and devices may comprise more than one proinflammatory pathway inhibitor. In some embodiments, the proinflammatory pathway inhibitor can prevent immunosuppressive cell recruitment. In some embodiments, the proinflammatory pathway inhibitor can prevent acute inflammation. In some embodiments, the proinflammatory pathway inhibitor can inhibit an immune response, e.g., to induce inflammation, including, e.g., production of one or more proinflammatory cytokines (e.g., TNF- α, IL-1 β, and/or IL-6), increase activity and/or proliferation of Th1 cells, recruitment of bone marrow cells, etc. For example, in some embodiments, the proinflammatory pathway inhibitor can be an IL-1 β inhibitor. In some embodiments, the proinflammatory pathway inhibitor can be an IL-6 inhibitor.
In certain embodiments, the proinflammatory pathway inhibitor is an inhibitor of a proinflammatory immune response mediated by a p38 mitogen-activated protein kinase (MAPK) pathway as described herein.
In certain embodiments, the proinflammatory pathway inhibitor prevents immunosuppressive cell recruitment. In certain embodiments, the proinflammatory pathway inhibitor is an inhibitor, antagonist, or partial agonist of CCR2, CCR5, CXCR2, CXCR4, CXCL12, or CCL 2. In certain embodiments, the proinflammatory pathway inhibitor is an inhibitor, antagonist, or partial agonist of CCR5, CXCR2, CXCL12, or CCL 2.
In certain embodiments, the proinflammatory pathway inhibitor is an inhibitor, antagonist, or partial agonist of CCR 2. In certain embodiments, CCR2 relates to the p38 MAPK pathway (e.g., as described in Montague et al, j. infilammation 2018, 15: 101; and Xu et al, am. j. trans. res.2017,9, 2878-2890). In certain embodiments, the inhibitor, antagonist, or partial agonist of CCR2 is PF-04136309, CCX872-B, or plozalizumab. In certain embodiments, the proinflammatory pathway inhibitor is PF-04136309, CCX872-B, or plozalizumab. In certain embodiments, the proinflammatory pathway inhibitor is not an inhibitor, antagonist, or partial agonist of CCR 2. In certain embodiments, the proinflammatory pathway inhibitor is not PF-04136309.
In certain embodiments, the proinflammatory pathway inhibitor is an inhibitor, antagonist, or partial agonist of CCR 5. In certain embodiments, CCR5 is involved in the p38 MAPK pathway (e.g., as described in Lei, et al., biochem. Biophys. Res. Commun.2005,329, 610-615; and Manes, et al., J.exp. Med.2003,198, 1381-1389). In certain embodiments, the inhibitor, antagonist, or partial agonist of CCR5 is maraviroc, DAPTA, GSK706769, INCB009471, GW873140, vicrivaroc, or PRO 140. In certain embodiments, the proinflammatory pathway inhibitor is maraviroc, DAPTA, GSK706769, INCB009471, GW873140, Vicriviroc, or PRO 140.
In certain embodiments, the proinflammatory pathway inhibitor is an inhibitor, antagonist, or partial agonist of CCR2 and CCR 5. In certain embodiments, the inhibitor, antagonist, or partial agonist of CCR2 and CCR5 is PF-04634817, cericiviroc, or BMS-813160. In certain embodiments, the proinflammatory pathway inhibitor is PF-04634817, ceriviroc, or BMS-813160.
In certain embodiments, the proinflammatory pathway inhibitor is an inhibitor, antagonist, or partial agonist of CXCR 2. In certain embodiments, the inhibitor, antagonist, or partial agonist of CXCR2 is danirixin, QBM076, SX-682, or SB 225002. In certain embodiments, the proinflammatory pathway inhibitor is danirixin, QBM076, SX-682, or SB 225002.
In certain embodiments, the proinflammatory pathway inhibitor is an inhibitor, antagonist, or partial agonist of CXCR 4. In certain embodiments, CXCR4 is involved in the p38 MAPK pathway (e.g., as described in Lei, et al., biochem. Biophys. Res. Commun.2005,329, 610-615; and Trushin, et al., J.Immunol.2007,178, 4846-4853). In certain embodiments, the inhibitor, antagonist, or partial agonist of CXCR4 is plerixafor, AMD070, AMD3465, AMD11070, LY2510924, MSX-122, TG-0054, CX-01, X4P-001, BL-8040, USL311, or SP 01A. In certain embodiments, the proinflammatory pathway inhibitor is plerixafor, AMD070, AMD3465, AMD11070, LY2510924, MSX-122, TG-0054, CX-01, X4P-001, BL-8040, USL311, or SP 01A. In certain embodiments, the proinflammatory pathway inhibitor is not an inhibitor, antagonist, or partial agonist of CXCR 4.
In certain embodiments, the proinflammatory pathway inhibitor is an inhibitor, antagonist, or partial agonist of CXCL 12. In certain embodiments, CXCL12 is involved in the p38 MAPK pathway (e.g., Gao, et al, int.j.clin.exp.pathol.2018,11,3119-3125 as described below).
In certain embodiments, the proinflammatory pathway inhibitor is an inhibitor, antagonist, or partial agonist of CCL 2. In certain embodiments, CCL2 is involved in the p38 MAPK pathway (e.g., as described in Cho, et al., J.Neurohimunol.2008, 199, 94-103; and Marra, et al., am.J.Physiol.Gastrointest.Liver Physiol.2004,287, G18-26). In certain embodiments, the inhibitor, antagonist, or partial agonist of CCL2 is bindarit.
In certain embodiments, the proinflammatory pathway inhibitor is PF-04136309, CCX872-B, plozalizumab, maraviroc, DAPTA, GSK706769, INCB009471, GW873140, Vicriviroc, PRO 140, PF-04634817, cenicriviroc, BMS-813160, danirixin, QBM076, SX-682, SB225002, plerixafor, AMD070, AMD3465, AMD11070, LY2510924, MSX-122, TG-0054, CX-01, X4P-001, BL-8040, USL311, or SP 01A.
In certain embodiments, the proinflammatory pathway inhibitor is CCX872-B, plozalizumab, maraviroc, DAPTA, GSK706769, INCB009471, GW873140, Vicriviroc, PRO 140, PF-04634817, cenicriviroc, BMS-813160, danirixin, QBM076, SX-682, SB225002, plerixafor, AMD070, AMD3465, 110AMD 70, LY2510924, MSX-122, TG-0054, CX-01, X4P-001, BL-8040, USL311, or SP 01A.
In certain embodiments, the proinflammatory pathway inhibitor prevents acute inflammation. In certain embodiments, the proinflammatory pathway inhibitor is an anti-IL-1 α antibody, an anti-IL-1 β antibody, an anti-IL-1R antibody, an IL-1 inhibitor, an anti-IL-6 antibody, an anti-IL-6R antibody, an anti-IL 17 antibody, an anti-IL-17A antibody, an anti-IL-17 RA antibody, an anti-IL-23/IL-12 antibody, or an anti-IL-23 antibody.
In certain embodiments, the proinflammatory pathway inhibitor is an anti-IL-1 α antibody. In certain embodiments, the anti-IL-1 α antibody is mab 1. In certain embodiments, the proinflammatory pathway inhibitor is mab 1.
In certain embodiments, the proinflammatory pathway inhibitor is an anti-IL-1 β antibody. In certain embodiments, IL-1 β is involved in the p38 MAPK pathway (e.g., as described in Kulawik, et al, J.biol.Chem.2017,292, 6291-6302; Rovin, et al, Cytokine 1999,11, 118-126; Laporte, et al, am.J.Physiol.LungCell. mol.Physiol.2000,279, L932-L941; Baldasare, et al, J.Immunol.1999,162, 5367-5373; and Weber, et al. Sci.Signal.2010,3, cm 1). In certain embodiments, the anti-IL-1 β antibody is conatinumab. In certain embodiments, the proinflammatory pathway inhibitor is conatinumab.
In certain embodiments, the proinflammatory pathway inhibitor is an anti-IL-1R antibody. In certain embodiments, IL-1R is involved in the p38 MAPK pathway (e.g., as described in: Weber, et al., Sci.Signal.2010,3, cm 1; and Jain, et al., nat. Commun.2018, 9: 3185). In certain embodiments, the anti-IL-1R antibody is anakinra. In certain embodiments, the proinflammatory pathway inhibitor is anakinra.
In certain embodiments, the proinflammatory pathway inhibitor is an IL-1 inhibitor. In certain embodiments, the IL-1 inhibitor is linagliptin. In certain embodiments, the proinflammatory pathway inhibitor is linaglip.
In certain embodiments, the proinflammatory pathway inhibitor is an anti-IL-6 antibody. In certain embodiments, IL-6 is involved in the p38 MAPK pathway (e.g., as described in Sinfield, et al, biochem. Biophys. Res. Commun.2013,430, 419-424; Suzuki, et al, FEBS Lett.2000,465, 23-27; and Nishikai-Yan Shen, et al, PLoS One 2017,12, 1-17). In certain embodiments, the anti-IL-6 antibody is olokizumab, clazakizumab, OPR-003, sirukumab, ARGX-109, FE301, or FM 101. In certain embodiments, the proinflammatory pathway inhibitor is olokizumab, clazakizumab, OPR-003, sirukumab, ARGX-109, FE301, or FM 101.
In certain embodiments, the proinflammatory pathway inhibitor is an anti-IL-6R antibody. In certain embodiments, the anti-IL-6R antibody is truzumab, sarilumab, or vobarilizumab. In certain embodiments, the proinflammatory pathway inhibitor is torilizumab, sarilumab, or vobarilizumab.
In certain embodiments, the proinflammatory pathway inhibitor is an anti-IL-17 antibody. In certain embodiments, IL-17 is involved in the p38 MAPK pathway (e.g., as described in Noubade, et al., Blood2011,118, 3290-3300; Roussel, et al., J.Immunol.2010,184, 4531-4537; and Mai, et al., J.biol.chem.2016,291, 4939-4954). In certain embodiments, the anti-IL-17 antibody is ixekizumab, bimekizumab, ALX-0761, CJM112, CNTO6785, LY3074828, SCH-900117, or MSB 0010841. In certain embodiments, the proinflammatory pathway inhibitor is ixekizumab, bimekizumab, ALX-0761, CJM112, CNTO6785, LY3074828, SCH-900117, or MSB 0010841.
In certain embodiments, the proinflammatory pathway inhibitor is an anti-IL-17A antibody. In certain embodiments, the anti-IL 17A antibody is secukinumab. In certain embodiments, the proinflammatory pathway inhibitor is secukinumab.
In certain embodiments, the proinflammatory pathway inhibitor is an anti-IL-17 RA antibody. In certain embodiments, the anti-IL 17RA antibody is brodalumab. In certain embodiments, the proinflammatory pathway inhibitor is brodalumab.
In certain embodiments, the proinflammatory pathway inhibitor is an anti-IL-23/IL-12 antibody. In certain embodiments, the anti-IL-23/IL-12 antibody is Ultezumab or brakinumab. In certain embodiments, the proinflammatory pathway inhibitor is eculizumab or briakumumab.
In certain embodiments, the proinflammatory pathway inhibitor is an anti-IL-23 antibody. In certain embodiments, IL-23 is involved in the p38 MAPK pathway (e.g., as described in Tang, et al., Immunology 2012,135, 112-124; and Anavese, et al., J.Clin.Exp.Dermatol.Res.2011, S2: 002. doi: 10.4172/2155-9554). In certain embodiments, the anti-IL-23 antibody is tiltrakizumab, BI 655066, or guselkumab. In certain embodiments, the proinflammatory pathway inhibitor is tiltrakizumab, BI 655066, or guselkumab.
In certain embodiments, the proinflammatory pathway inhibitor is MABp1, conatinab, anakinra, linazept, olokizumab, clazakizumab, OPR-003, sirukumab, ARGX-109, FE301, FM101, torilizumab, sarilumab, vobrilizumab, ixekizumab, bimekizumab, ALX-0761, CJM112, CNTO 6785, LY3074828, SCH-900117, MSB0010841, secukinumab, brodalumab, Ultkukumab, brikinumab, tiltrakizumab, BI 655066, or gusekilumab.
In certain embodiments, the proinflammatory pathway inhibitor is a TGF β R inhibitor. In certain embodiments, the TGF β R is involved in the p38 MAPK pathway (e.g., as described in Yu et al, EMBO J.2002,21, 3749-3759; Sato, et al, J.invest.Dermatol.2002,118, 704-711; and Hanafusa, et al, J.biol.chem.1999,274, 27161-27167). In certain embodiments, the TGF β R inhibitor is galinisertib. In certain embodiments, the proinflammatory pathway inhibitor is galinisertib.
In certain embodiments, the proinflammatory pathway inhibitor is or comprises a Specific Proresolvingmediator (SPM). SPM is a long chain fatty acid-derived lipid mediator involved in the coordinated resolution process of preventing excessive inflammation and/or resolving an acute inflammatory response. Examples of such SPMs include, for example, Arachidonic Acid (AA) -derived lipoxins and docosahexaenoic acid (DHA) -derived resolvins. Regression is an active process involving the generation of molecules that signal through specific cell surface receptors to regulate inflammation, enhance endocytosis, and repair tissue damage without compromising host defense. See, e.g., Caiet al, "MerTK clean limits boosting mediator synthesis and exarbaterestissue information" PNAS, 113: 6526-6531 (2016); andSerhan et al, "Novel anti-inflammatory-Pro-quenching mediators and the receptors" Curr Top Med Chem 11: 629-647(2011). Cyclooxygenase enzymes (e.g., COX-2) may be involved in the production of certain SPMs.
In some embodiments, an SPM that can be used as an inhibitor of a pro-inflammatory pathway is or includes resolvin. Resolvins have been shown to enhance tumor cell debris clearance by macrophage phagocytosis and to counter-regulate cytokines/tropismsRelease of chemokines includes, for example, TNF α, IL-6, IL-8, CCL4, and/or CCL 5. See, e.g., Sulciner et al, "resolution supports grow and enhance cancer therapy" J Exp Med 215: 115-140(2018). Resolvins (Rvs) are classified into the following classes: resolvins Ds (RvDs), derived from docosahexaenoic acid (DHA); regressins Es (RvEs) derived from eicosapentaenoic acid (EPA); resolvin Dn-6DPA(RvDn-6DPA) Derived from DPA isomers, osbonic acids; resolvin Dn-3DPA(RvDn-3DPA) From DPA isomer, docosapentaenoic acid; regressins Ts (RvTs) derived from RvDn-3DPAA different docosapentaenoic acid (having a 17S-hydroxy residue) having a 17R-hydroxy residue. One skilled in the art will appreciate that in some cases resolvins may be or include RvD1, RvD2, RvD3, RvD4, RvD5, RvD6, 17R-RvD1, 17R-RvD2, 17R-RvD3, 17R-RvD4, 17R-RvD5, 17R-RvD6, RvE1, 18S-RvE1, RvE2, RvE3, RvT1, RvT2, RvT3, RvT4, RvD1 n-3，RvD2n-3，RvD5n-3Or a combination thereof.
In some embodiments, SPMs that are useful as pro-inflammatory pathway inhibitors are or include lipoxins (including, e.g., LxA4, LxB4, 15-epi-LxA4, and/or 15-epi-LxB4), protectins/neuroprotectives (e.g., DHA-derived protectins/neuroprotectives and/or n-3 DPA-derived protectins/neuroprotectives), maresins (e.g., DHA-derived maresins and/or n-3 DPA-derived maresins), and other DPA metabolites.
Inhibitors of the p38 mitogen-activated protein kinase (MAPK) pathway-mediated pro-inflammatory immune response
The present invention recognizes, among other things, that inhibiting a pro-inflammatory immune response mediated by a p38 mitogen-activated protein kinase (MAPK) pathway at a target site (e.g., a tumor resection site) (e.g., by administering a p38 MAPK inhibitor to modulate (e.g., inhibit) a p38 MAPK-mediated pro-inflammatory pathway or component thereof; see, e.g., fig. 4-6) can reduce the risk of cancer recurrence and thus prolong survival. Unexpectedly, inhibition of MAPK may enhance anti-tumor immunity since therapies that target MAPK (e.g., inhibition of the BRAF/MEK/ERK module) are reported to induce transcriptional profiles associated with blockade of therapy resistance against PD-1 immune checkpoints, which in turn may adversely affect responsiveness to anti-PD-1/L1 cancer therapies (see, e.g., Hugo et al, Cell 2016, 165, 35-44).
Accordingly, in some embodiments, provided herein are drug delivery compositions and devices comprising an inhibitor of the pro-inflammatory immune response mediated by the p38 mitogen-activated protein kinase (MAPK) pathway. In some embodiments, the drug delivery compositions and devices provided herein may comprise more than one inhibitor of the pro-inflammatory immune response mediated by the p38 mitogen-activated protein kinase (MAPK) pathway.
The p38 family of MAPKs includes the p38 α, p38 β, p38 γ and the p38 isoforms. p38 MAPK are activated by a number of immune receptors, so inhibition of signaling modules or regulatory targets acting upstream or downstream of p38 may provide an effective and selective means of inhibiting molecular pathways and their mediated pro-inflammatory immune responses.
For example, p38 MAPK may be mitogen-activated protein kinase 3(MAP2K3), mitogen-activated protein kinase 6(MAP2K6), mitogen-activated protein kinase 1(MAP3K1) and/or mitogen-activated protein kinase 4(MAP3K 4). Therefore, inhibition of the upstream target of the p38 MAPK may be effective in inhibiting the p38 MAPK pathway.
Inhibition of downstream targets of the p38 MAPK may also be an effective way to inhibit the p38 MAPK pathway. Downstream of the p38 MAPK, for example, protein kinases 1 and 2(MNK1 and MNK2) that interact with mitogen-activated protein kinases are activated via the p38 MAPK pathway. MNK kinases play an important role in regulating mRNA translation and are therefore key mediators of oncogenic progression, drug resistance, pro-inflammatory cytokine production and cytokine signaling. Mitogen and stress activated kinases 1 and 2(MSK1 and MSK2) are also downstream targets of the p38 MAPK and affect inflammatory responses. MAP kinase activated protein kinases 2, 3 and 5(MK2, MK3, MK5) are activated by p38 MAPK and are involved in cellular stress and inflammatory responses.
In view of the foregoing, inhibition of the p38 MAPK pathway may provide a therapeutic strategy for cancer treatment. In particular, local inflammatory wound reactions and systemic inflammatory processes may co-activate dormant micrometastases or induce residual cancer cell spread, thereby increasing the risk of cancer recurrence. Thus, inhibition of the pro-inflammatory immune response mediated by the p38 MAPK pathway at the site of tumor resection can reduce the risk of cancer recurrence and prolong survival of the subject.
In certain embodiments, the inhibitor of a p38 MAPK pathway-mediated pro-inflammatory immune response is a p38MAP kinase inhibitor. In certain embodiments, the p38MAP kinase inhibitor is an inhibitor of p38 α, p38 β, p38 γ, and/or p38MAP kinase. In certain embodiments, the p38MAP kinase inhibitor is Semalimod, pexmitinib, BMS-582949, loshapimod, pamapimod, ralimetinib, doramapimod, VX-702, VX-745, TAK-715, SB239063, SB202190, SB203580, SCIO 469, PH-797804, AZD7624, ARRY-797, ARRY-614, AVE-9940, LY3007113, skeperinone-L, UM-164, SCIO 323, SX-011, SK-F860002, SB 6504, SB681323, CHF-6297, RWJ-67657, or g48762-0, RX3403, JX-401, EO-1428, 1281285, AMG-7097, PD-548, 709316, PF-03715455, DBMONONITALM 797804, Slonimod 797804, 169651, sorafenib, or 16sela. In certain embodiments, the p38MAP kinase inhibitor comprises a quinazolinone, pyrimido-pyrimidone, pyrido-pyrimidone, pyrazole, quinolinone, and/or naphthyridone core structure. In certain embodiments, the p38MAP kinase inhibitor is loshapimod.
In certain embodiments, the inhibitor of a p38MAPK pathway-mediated pro-inflammatory immune response is a p38 α, p38 β, p38 γ, and/or p38MAP kinase inhibitor. In certain embodiments, the inhibitor of a pro-inflammatory immune response mediated by the p38MAPK pathway is Sesammod, pexmitinib, BMS-582949, loshapimod, pamapimod, ralimetinib, doramapimod, VX-702, VX-745, TAK-715, SB239063, SB202190, SB203580, SCIO 469, PH-797804, AZD7624, ARRY-797, ARRY-614, AVE-9940, LY3007113, skeperinone-L, UM-164, SCIO323, SX-011, SK-F860002, SB706504, SB681323, CHF-6297, RWJ-67657, or g48762-0, ML 6813, JX-401, EO-1428, AMG 1285, AMG-PD, DBMA-8697, DBMA-9316, sorafei-9383, SERP-366335, SULPIDINb, or Slimab. In certain embodiments, the inhibitor of a p38MAPK pathway-mediated pro-inflammatory immune response comprises a quinazolinone, pyrimidinone, pyrido-pyrimidinone, pyrazole, quinolinone, and/or naphthyridone core structure. In certain embodiments, the inhibitor of a p38MAPK pathway-mediated pro-inflammatory immune response is loshapimod.
In certain embodiments, the p38MAP kinase inhibitor binds to the ATP binding site of at least one p38MAP kinase (e.g., p38 α, p38 β, p38 γ, and/or p38MAP kinase). In certain embodiments, the p38MAP kinase inhibitor is an allosteric inhibitor of at least one p38MAP kinase (e.g., p38 α, p38 β, p38 γ, and/or p38MAP kinase).
In certain embodiments, the inhibitor of a pro-inflammatory immune response mediated by the p38 MAPK pathway is an inhibitor of an upstream effector of the p38 MAPK. In certain embodiments, the inhibitor of a p38 MAPK pathway-mediated pro-inflammatory immune response is an inhibitor of: RIPK1, RIPK2, RIPK3, RIPK4, RAC1, CDC42, MTK1, TAK1, MEKK1, MEKK2, MEKK3, MEKK4, DLK, MLK2, TAO1, TAO2, TLP2, TPL2, ASK1, MKK3, MKK4, and/or
In some embodiments, one of skill in the art will recognize that an inhibitor of a p38 MAPK pathway-mediated pro-inflammatory immune response (e.g., a p38 MAPK inhibitor) can modulate (e.g., inhibit) the activity and/or expression of Cyclooxygenase (COX) -1 and/or COX-2. See, e.g., Matsuiet al, "Release of prostaglandin E2and nitricoxide from spinal microglia is dependent on activation of p38 mitogen-activated protein kinase”Anesthesia&Analgesia,111(2)：554-560(2010)。
In some embodiments, one of skill in the art will recognize that certain COX inhibitors (e.g., COX-1 and/or COX-2 inhibitors) and/or other anti-inflammatory agents (e.g., Non-steroidal anti-inflammatory drugs (NSAIDs) and/or anti-inflammatory analgesics) may be used as modulators (e.g., inhibitors) of the p38 MAPK pathway or components thereof (see, e.g., as described in: an affinity assay, "Non-steroidal anti-inflammatory drug-affinity drivers in Parkinson's disease" Experimental nervous pathway 205: 295-312 (2007); Desai et al, "Mechanisms of molecular Modulation of cytokine-2 (COX-2) and inflammatory reaction promoter" nucleic and Cancer, 70: 350-375 (2018); and "tissue/COX in injection therapy-2 and inflammatory receptor of VEGF-expressed tissue-receptor" VEGF-1, 6: 2129-2136 (2013); and Di Mari et al, "HETES enhance IL-1-mediated COX-2expression visualization of message status in human collagen mybiology" Am JPhysiol-gastroenterest liverphysiol, 293: 2092-2101(2007)). Thus, in some embodiments, a COX-2 inhibitor or other anti-inflammatory agent can be (and/or can be used as) a p38 MAPK inhibitor described herein; alternatively, or additionally, in some embodiments, such COX inhibitors or other anti-inflammatory agents may be used in combination with another p38 MAPK inhibitor described herein.
In some embodiments, the COX inhibitor may be a non-selective COX-1 and/or COX-2 inhibitor. In some embodiments, the COX inhibitor may be a selective COX-1 and/or COX-2 inhibitor.
In some embodiments, certain COX inhibitors that can be used as p38MAPK pathway inhibitors (i.e., inhibitors of the p38MAPK pathway or components thereof) include, but are not limited to, inhibitors non-steroidal anti-inflammatory drugs (NSAIDs). In some embodiments, NSAIDs can reduce inflammation by inhibiting the activity of cyclooxygenase enzymes (COX-1 and/or COX-2), which are commonly involved in the production of prostaglandins that are involved in inflammation.
In some embodiments, the NSAID used as a p38MAPK pathway inhibitor is or includes celecoxib, which is generally recognized as a selective COX-2 inhibitor. See, for example, Chen et al, "Celexib inhibition of the lytic activation of Kaposi's sarcoma-associated human virus through-down-regulation of RTA expression by inhibition of the activation of p38 MAPK" Viruses 7: 2268-2287 (2015); and Fan et al, "Celeboxib substrates systems lipid-induced polyamide in migration and white substrate in circulation in the circulation rates" Neuroscience 240: 27-38(2013).
In some embodiments, the NSAID used as a p38 MAPK pathway inhibitor is or includes ketorolac. Ketorolac is thought to inhibit prostaglandin synthesis, for example, by competitively blocking COX enzymes. In some embodiments, ketorolac reduces the expression of IL-6. See, for example, Singh et al, "A productive student to access the levelsof interface-6 following addition of dichotomac, Ketorolac and tramalolafter scientific removal of lower third molar" J.Maxillofac Oral Surg.14: 219-225(2015). One skilled in the art will also appreciate that ketorolac may be used as a non-selective COX inhibitor with known anti-inflammatory properties. However, without wishing to be bound by a particular theory, in some embodiments ketorolac may be considered to have a higher selectivity for inhibiting COX-1 over COX-2 (see Hersh and dione "Nonopioid industries" in pharmacology and Therapeutics for delivery (7th edition), Dowd et al, elseviere.2017). Ketorolac is routinely used for short-term pain control and therefore is not typically prescribed for more than 5 days. In some embodiments, the ketorolac used in the present disclosure is released from the biological material (e.g., as described herein) over a period of time as follows: at least 5 days or more, e.g., at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, or more, thereby inhibiting or reducing immunosuppressive inflammation induced by tumor resection surgery. Ketorolac may be administered as a racemic mixture or as an individual enantiomer (e.g., the S-enantiomer).
Other examples of NSAIDs useful in the present disclosure include, but are not limited to, (i) salicylates (e.g., acetylsalicylic acid, diflunisal, salicylic acid and other salicylates, and/or salsalate); (ii) (ii) a propionic acid derivative (e.g., ibuprofen, dexiburofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin and/or loxoprofen), (iii) an acetic acid derivative (e.g., indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, aceclofenac, and/or naproxone), (iv) an enolic acid (oxicam) derivative (e.g., piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam and/or phenylbutazone), (v) an o-oxicam derivative or fenamate (e.g., mefenamic acid, meclofenamic acid, flufenamic acid and/or tolfenamic acid), (v) a selective COX-2 inhibitor (e.g., celecoxib, rofecoxib, dioxib, parecoxib, romycin, lumiracoxib, etoricoxib and/or fenocoxib) (vii) an aniline (vi), nimesulide); (viii) others (e.g., lonicin, licofelone [ e.g., acting by inhibiting Lipoxygenase (LOX) and COX ] and/or H-harpagide), and combinations thereof.
As one of skill in the art will recognize, in some embodiments, a p38 MAPK inhibitor may modulate (e.g., inhibit) the Wnt- β -catenin pathway or a component thereof, e.g., as shown in fig. 5 and in Bikkavilli et al, "p 38 mitogen-activated protein kinase regulation of systemic Wnt- β -catenin by activation of GSK3 β" Journal of Cell Science, 121: 3598-3607 (2008). Thus, in some embodiments, the inhibitor of a pro-inflammatory immune response mediated by the p38 MAPK pathway may be or comprise a Wnt inhibitor. In some embodiments, the inhibitor of a pro-inflammatory immune response mediated by the p38 MAPK pathway may be or comprise a GSK3 β inhibitor. In some embodiments, the inhibitor of a pro-inflammatory immune response mediated by the p38 MAPK pathway may be or comprise a β -catenin inhibitor.
It will also be appreciated by those skilled in the art that certain Wnt/β -catenin pathway inhibitors may be useful as modulators (e.g., inhibitors) of the p38 MAPK pathway or components thereof (see, e.g., Andre et al, "Wnt 5a and Wnt11 regulatory major antigen-compressor interaction" Development 142: 1516-1527 (2015); and Ma et al, "Crosstalk beta Wnt/β -catenin and NF- κ Bsingling pathway double injection" Front immune.7: 378 (2016)). Thus, in some embodiments, a Wnt/β -catenin pathway inhibitor may be (and/or may be used as) a p38 MAPK inhibitor described herein; alternatively, or additionally, in some embodiments, such Wnt/β -catenin pathway inhibitors may be used in combination with another p38 MAPK inhibitor described herein.
Innate immune response activators
The drug delivery compositions and devices may comprise innate immune response activators. Drug delivery compositions and devices may comprise more than one innate immune response activator. The primary function of the innate immune response includes the recruitment of immune cells to the site of infection by the production of chemical factors, including specific chemical mediators (e.g., cytokines); activating the complement cascade to recognize bacteria, activate cells, and facilitate clearance of antibody complexes or dead cells; recognizing and removing foreign substances present in organs, tissues, blood and lymph by specific leukocytes; activation of the adaptive immune system by a process known as antigen presentation; and as physical and chemical barriers for infectious agents (e.g., epithelial surfaces, gastrointestinal tract). Generally, leukocytes are white blood cells that achieve the effects of the innate immune system. These cells include natural killer cells, mast cells, eosinophils, basophils, macrophages, neutrophils, and dendritic cells. These cells function in the immune system by recognizing and eliminating pathogens that may cause infection.
In certain embodiments, the innate immune response activator is a ligand for a Pattern Recognition Receptor (PRR).
In certain embodiments, the innate immune response activator is an agonist of a Pattern Recognition Receptor (PRR).
In certain embodiments, the innate immune response activator is an inducer of type I interferon. In certain embodiments, the innate immune response activator is a recombinant interferon.
In certain embodiments, the innate immune response activator is an effective inducer of activation and/or proliferation of NK cells. In certain embodiments, an "effective inducer" refers to an activator of the innate immune response that directly induces activation and/or proliferation of NK cells.
In certain embodiments, the innate immune response activator is an effective inducer of activation and/or maturation of dendritic cells. In certain embodiments, an "effective inducer" refers to an activator that directly induces an innate immune response of activation and/or maturation of dendritic cells.
In certain embodiments, the innate immune response activator is an effective inducer of type I interferon by dendritic cells. In certain embodiments, an "effective inducer" refers to an activator of the innate immune response of type I interferon directly induced by dendritic cells.
In certain embodiments, the innate immune response activator is a small molecule or biologic. In certain embodiments, the innate immune response activator is a small molecule. In certain embodiments, the innate immune response activator is a biological agent.
In certain embodiments, the innate immune response activator is an interferon gene Stimulator (STING) agonist, a Cytosolic DNA Sensor (CDS) agonist, a Toll-like receptor (TLR) agonist, a C-type lectin receptor (CLR) agonist, a NOD-like receptor (NLR) agonist, a RIG-I-like receptor (RLR) agonist, or an inflammatory body inducer.
In certain embodiments, the innate immune response activator is an interferon gene Stimulator (STING) agonist, a Toll-like receptor (TLR) agonist, or a NOD-like receptor (NLR) agonist. In certain embodiments, the innate immune response activator is an interferon gene Stimulator (STING) agonist or a Toll-like receptor (TLR) agonist. In certain embodiments, the innate immune response activator is an interferon gene Stimulator (STING) agonist, a TLR7 agonist, or a TLR8 agonist.
In certain embodiments, the innate immune response activator is 3 '3' -cGAMP, 2 '3' -cGAMP, 2 '3' -cGAM (PS)2(Rp/Rp), 2 '3' -cGAM (PS)2(Rp/Sp), 2 '2' -cGAMP, c-di-AMP, 2 '3' -c-di-AMP, 2 '3' -c-di-AMP (PS)2(Rp/Rp), 2 '3' -c-di-AMP (PS)2(Rp/Sp), c-di-GMP, c-di-IMP, HSV-60, ISD, VACV-70, poly (dA: dT), poly (dG: dC), heat killed bacteria, Lipopolysaccharide (LPS), lipoteichoic acid, Peptidoglycan (PGNs), synthetic lipoprotein, poly (AU: U), poly (I: C), monophosphoryl lipid A (MPLA), GSK1795091, G100, SD-101, MGN1703, CMP-001, Flagellin (FLA), poly U, poly (dT), gardiquimod, imiquimod (R837), a base analog, an adenosine analog, a guanosine analog, a purine derivative, a benzazepine analog, an imidazoquinoline, a thiazoloquinoline, loxoribine, resiquimod (R848), daculisib, sumanirole, N1-glycinyl [4- ((6-amino-2- (butylamino) -8-hydroxy-9H-purin-9-yl) methyl) benzoyl ] spermine (CL307), CL264, CL097, CL075, CL347, CL401, CL413, CL419, CL531, CL553, CL, MEDI9197, MEDI5083, hypoxanthine, TL8-506, Topo-32, SM-PF 39 324406, Airbeitin (R), AZ12441970, AZ12443988, CpG oligonucleotides, bacterial DNA, beta glycans from fungal and bacterial cell walls, gamma-D-Glu-mDAP (iE-DAP), iE-DAP derivatives, Muramyl Dipeptide (MDP), MDP derivatives, 5 ' double stranded RNA triphosphate, poly (dA: dT), ATP, chitosan, potassium aluminum sulfate, calcium pyrophosphate dehydrate, silica, MurNAc-L-Ala-gamma-D-Glu-mDAP (M-TriDAP), xanthone analogs (e.g., DMXAA; vadimezan), TREX1 inhibitors, cyclic di-nucleotides, LHC165, GSK-2245035, RG7854, GS-9620, GS-9688, EMD1201081, PF-3512676, BO-112, RGT-100, RGT-1454, SB-11285, NKTR-301, 2 ' 3 ' -c-GMP, cAIMP, cAIM (PS)2(Rp/Sp), derivatives thereof, or pharmaceutically acceptable salts thereof.
In certain embodiments, the innate immune response activator is a fluorinated derivative of any of the above activators. In certain embodiments, the innate immune response activator is activator cAIMP (c- (2 'FdAMP-2' FdAMP)). In certain embodiments, the innate immune response activator is difluorinated cAIM (PS)2 (Rp/Sp). In certain embodiments, the innate immune response activator is an O-methylated derivative of any of the above activators.
In certain embodiments, the activator of innate immune response is 3 '3' -cGAMP, 2 '3' -cGAMP, 2 '3' -cGAM (PS)2(Rp, Rp), 2 '3' -cGAM (PS)2(Rp, Sp), 2 '2' -cGAMP, c-di-AMP, 2 '3' -c-di-AMP, 2 '3' -c-di-AM (PS)2(Rp, Rp), 2 '3' -c-di-AM (PS)2(Rp, Sp), c-di-GMP, 2 '3' -c-di-GMP, 2 '3' -c-di-GM (PS)2(Rp, Rp), 2 '3' -c-di-GM (PS)2(Rp, IMP), c-di, resiquimod, a CpG oligonucleotide, polyinosinic acid: polycytidylic acid, LHC165, GSK-2245035, RG7854, GS-9620, GS-9688, EMD1201081, PF-3512676, BO-112, RGT-100, MK-1454, SB-11285, NKTR-262, CDX-301, 2 '3' -c-di-GMP, cAIMP, cAIM (PS)2(Rp/Sp), or a pharmaceutically acceptable salt thereof.
In certain embodiments, the innate immune response activator is a fluorinated derivative of: 3 '3' -cGAMP, 2 '3' -cGAMP, 2 '3' -cGAM (PS)2(Rp, Rp), 2 '3' -cGAM (PS)2(Rp, Sp), 2 '2' -cGAMP, c-di-AMP, 2 '3' -c-di-AMP, 2 '3' -c-di-AM (PS)2(Rp, Rp), 2 '3' -c-di-AM (PS)2(Rp, Sp), c-di-GMP, 2 '3' -c-di-GMP, 2 '3' -c-di-GM (PS)2(Rp, Rp), 2 '3' -c-di-GM (PS)2(Rp, IMPSp), c-di-GMP, 2 '3' -c-di-GMP, IMP, and RPcAIM (PS)2(Rp/Sp), or a pharmaceutically acceptable salt thereof.
In certain embodiments, the innate immune response activator is an O-methylated derivative of: 3 '3' -cGAMP, 2 '3' -cGAMP, 2 '3' -cGAM (PS)2(Rp, Rp), 2 '3' -cGAM (PS)2(Rp, Sp), 2 '2' -cGAMP, c-di-AMP, 2 '3' -c-di-AMP, 2 '3' -c-di-AM (PS)2(Rp, Rp), 2 '3' -c-di-AM (PS)2(Rp, Sp), c-di-GMP, 2 '3' -c-di-GMP, 2 '3' -c-di-GM (PS)2(Rp, Rp), 2 '3' -c-di-GM (PS)2(Rp, IMPSp), c-di-GMP, or a pharmaceutically acceptable salt thereof.
In certain embodiments, the innate immune response activator is 2 '3' -cGAMP, 2 '3' -c-di-AM (PS)2(Rp, Rp), MurNAc-L-Ala- γ -D-Glu-mDAP (M-TriDAP), c-di-GMP, or resiquimod. In certain embodiments, the innate immune response activator is 2 '3' -cGAMP, 2 '3' -c-di-AM (PS)2(Rp, Rp), MurNAc-L-Ala- γ -D-Glu-mDAP (M-TriDAP), or resiquimod. In certain embodiments, the innate immune response activator is 2 '3' -cGAMP, 2 '3' -c-di-AM (PS)2(Rp, Rp), or resiquimod. In certain embodiments, the innate immune response activator is 2 '3' -c-di-AM (PS)2(Rp, Rp) or resiquimod. In certain embodiments, the innate immune response activator is cAIMP or a fluorinated derivative thereof. In certain embodiments, the innate immune response activator is difluorinated cadimp.
In certain embodiments, the innate immune response activator is 2 '3' -cGAMP, or a pharmaceutically acceptable salt thereof. In particular, 2 '3' -cGAMP (cyclic [ G (2 ', 5') pA (3 ', 5') p ]) has been described as acting as an endogenous second messenger, including STING-dependent type I interferon responses. 2 '3' -cGAMP has also been shown to be a potent adjuvant for enhancing antigen-specific antibody production and T cell responses in mice. 2 '3' -cGAMP functions as an antiviral in the cell in which it is produced, but also functions across the cell membrane on neighboring cells by passive diffusion.
In certain embodiments, the innate immune response activator is 2 '3' -c-di-AM (PS)2(Rp, Rp), or a pharmaceutically acceptable salt thereof. 2 '3' -c-di-AM (PS)2(Rp, Rp) is the Rp, Rp-isomer of the 2 '3' -dithiophosphate analog of 3 '3' -cyclic adenosine monophosphate (c-di-AMP). It is also a STING agonist.
In certain embodiments, the innate immune response activator is cAIMP, a difluorinated derivative thereof, a difluorinated dithiophosphate derivative thereof (cAIM (PS)2(Rp/Sp)), or a pharmaceutically acceptable salt thereof. cAIMP and its derivatives are also STING agonists.
In certain embodiments, the activator of innate immune response is a STING agonist, wherein the STING agonist is a cyclic dinucleotide. In certain embodiments, the cyclic-di-nucleotide is any cyclic-di-nucleotide disclosed in U.S. patent application u.s.s.n.15/234,182 filed 2016, the entire contents of which are incorporated herein by reference. In certain embodiments, the cyclic-di-nucleotide is any cyclic-di-nucleotide disclosed in U.S. patent application u.s.s.n.14/362,441 filed 12, 16, 2014, which is incorporated herein by reference in its entirety.
In certain embodiments, the innate immune response activator is MK-1454.
In certain embodiments, the activator of innate immune response is a Cytosolic DNA Sensor (CDS) agonist. In certain embodiments, the CDS agonist is a cyclic GMP-AMP synthase (cGAS) agonist.
In certain embodiments, the innate immune response activator is any STING agonist or cGAS agonist disclosed in U.S. patent application u.s.s.n.14/653,586 filed on 2013, 12, 16, the entire contents of which are incorporated herein by reference. In certain embodiments, the innate immune response activator is any STING agonist or cGAS agonist disclosed in U.S. patent application u.s.s.n.14/268,967 filed 5/2 2014, which is incorporated herein by reference in its entirety. In certain embodiments, the innate immune response activator is any STING agonist or cGAS agonist disclosed in U.S. patent application u.s.s.n.14/787,611 filed 4/29 2014, which is incorporated herein by reference in its entirety. In certain embodiments, the innate immune response activator is any STING agonist or cGAS agonist disclosed in U.S. patent application u.s.s.n.14/908,019 filed on 31/7/2014, the entire contents of which are incorporated herein by reference.
In certain embodiments, the innate immune response activator is any STING agonist disclosed in U.S. patent application u.s.s.n.13/057,662 filed on 14.6.2011, the entire contents of which are incorporated herein by reference. In certain embodiments, the innate immune response activator is any STING agonist disclosed in U.S. patent application u.s.s.n.14/106,687 filed on 12/13 of 2013, the entire contents of which are incorporated herein by reference. In certain embodiments, the activator of innate immune response is any STING agonist disclosed in U.S. patent application u.s.s.n.15/035,432 filed on 2016, 5, 19, the entire contents of which are incorporated herein by reference. In certain embodiments, the innate immune response activator is any STING agonist disclosed in international patent application PCT/US2017/013049 filed on 11/1/2017, the entire contents of which are incorporated herein by reference. In certain embodiments, the innate immune response activator is any STING agonist disclosed in international patent application PCT/US2017/013066 filed on 11/1/2017, the entire contents of which are incorporated herein by reference. In certain embodiments, the innate immune response activator is any STING agonist disclosed in international patent application PCT/US2014/038525 filed 5/18 2014, the entire contents of which are incorporated herein by reference. In certain embodiments, the innate immune response activator is any STING agonist disclosed in U.S. patent application u.s.s.n.13/912,960 filed on 7.6.2013, the entire contents of which are incorporated herein by reference. In certain embodiments, the activator of innate immune response is any STING agonist disclosed in international patent application PCT/IB2016/057265 filed on 12/1/2016, the entire contents of which are incorporated herein by reference.
In certain embodiments, the innate immune response activator is MurNAc-L-Ala- γ -D-Glu-mDAP (M-TriDAP), or a pharmaceutically acceptable salt thereof. M-TriDAP is a Peptidoglycan (PGN) degradation product that is primarily found in gram-negative bacteria. M-TriDAP is recognized by the intracellular sensor NOD1(CARD4) and to a lesser extent by NOD2(CARD 15). Recognition of M-TriDAP by NOD1/NOD2 induces an amplification of a signaling cascade involving serine/threonine RIP2(RICK, CARDIAK) kinase, which interacts with IKK, resulting in activation of NF-. kappa.B and production of inflammatory cytokines such as TNF-. alpha.and IL-6. M-TriDAP induces NF- κ B activation at a level similar to that of Tri-DAP.
In certain embodiments, the innate immune response activator is a TLR7 agonist. In certain embodiments, the innate immune response activator is a TLR8 agonist. In certain embodiments, the innate immune response activator is a TLR7 agonist and a TLR8 agonist.
In certain embodiments, the innate immune response activator is an Immune Response Modifier (IRM).
In certain embodiments, the innate immune response activator is any IRM disclosed in U.S. patent application u.s.s.n.08/620,779 filed 3/22 1996, which is incorporated herein by reference in its entirety. In certain embodiments, the innate immune response activator is any IRM disclosed in U.S. patent application u.s.s.n.08/957,192 filed 24/10/1997, the entire contents of which are incorporated herein by reference. In certain embodiments, the innate immune response activator is any IRM disclosed in U.S. patent application u.s.s.n.09/528,620 filed 3/20/2000, the entire contents of which are incorporated herein by reference. In certain embodiments, the innate immune response activator is any IRM disclosed in U.S. patent application u.s.s.n.06/798,385 filed 11/15 1985, the entire contents of which are incorporated herein by reference. In certain embodiments, the innate immune response activator is any IRM disclosed in U.S. patent application u.s.s.n.08/303,216 filed on 8.9/1994, the entire contents of which are incorporated herein by reference. In certain embodiments, the innate immune response activator is any IRM disclosed in U.S. patent application u.s.s.n.09/210,114 filed 12/11 of 1998, the entire contents of which are incorporated herein by reference. In certain embodiments, the innate immune response activator is any IRM disclosed in U.S. patent application u.s.s.n.09/361,544 filed 27.7.1999, the entire contents of which are incorporated herein by reference. In certain embodiments, the innate immune response activator is any IRM disclosed in international patent application PCT/US2004/032480 filed 10/1 of 2004, the entire contents of which are incorporated herein by reference.
In certain embodiments, the innate immune response activator is CL307 (N1-glycinyl [4- ((6-amino-2- (butylamino) -8-hydroxy-9H-purin-9-yl) methyl) benzoyl ] spermine), or a pharmaceutically acceptable salt thereof. CL307 is a very potent TLR7 agonist. Titration experiments have demonstrated that CL307 induces potent NF-. kappa.B activation even at concentrations as low as 20nM (10 ng/ml).
In certain embodiments, the innate immune response activator is CL264, or a pharmaceutically acceptable salt thereof. CL264 induces the activation of NF-. kappa.B and the secretion of IFN-. alpha.in cells expressing TLR 7. CL264 is a TLR7 specific ligand, which does not stimulate TLR8 even at high concentrations (>10 μ g/ml). CL264 triggered NF- κ B activation at a concentration of 0.1 μ M in TLR 7-transfected HEK293 cells, which was 5-10 fold lower than imiquimod.
In certain embodiments, the innate immune response activator is loxoribine, or a pharmaceutically acceptable salt thereof. The loxoribine is in N7And C8A derivatized guanosine analog at a position. This nucleotide is a very powerful stimulator of the immune system. Loxoribine activates the innate immune system through TLR7, which requires endosomal maturation. Loxoribine recognition is limited to TLR 7.
In certain embodiments, the innate immune response activator is hypoxanthine, or a pharmaceutically acceptable salt thereof. Hypoxanthine is a natural purine derivative.
In certain embodiments, the innate immune response activator is TL8-506, or a pharmaceutically acceptable salt thereof. TL8-506 is a benzazepine compound, an analog of the Toll-like receptor 8(TLR8) agonist VTX-2337. TL8-506 activates TLR8 more potently than R848 and CL 075. TL8-506 was about 50-fold and 25-fold more potent in inducing NF-. kappa.B activation in TLR8 transfected HEK293 cells, respectively, than R848 and CL 075. TL8-506 is a selective agonist for TLR 8.
In certain embodiments, the innate immune response activator is PF-4878691, etoricine, SM-324405, SM-324406, AZ12441970, AZ12443988, GSK-2245035, RG7854, GS-9620, LHC165, NKTR-262, GS-9688, VTX-2337, or a pharmaceutically acceptable salt thereof. PF-4878691, etoricine, SM-324405, SM-324406, AZ12441970, AZ12443988, GSK-2245035, RG7854, and GS-9620 are TLR7 agonists. LHC165 and NKTR-262 are agonists of both TLR7 and TLR8 agonists. GS-9688 and VTX-2337 are TLR8 agonists.
In certain embodiments, the innate immune response activator is an imidazoquinoline derivative, including daculisib, imiquimod, gardiquimod, resiquimod, sumanirole, and pharmaceutically acceptable salts thereof.
In certain embodiments, the innate immune response activator is CL097, or a pharmaceutically acceptable salt thereof. CL097 is the highly water soluble derivative resiquimod (≧ 20 mg/ml). CL097 is a TLR7 and TLR8 ligand. It induces activation of NF-. kappa.B at the following levels: 0.4 μ M (0.1 μ g/ml) in TLR7 transfected HEK293 cells and 4 μ M (1 μ g/ml) in TLR8 transfected HEK293 cells.
In certain embodiments, the innate immune response activator is CL075, or a pharmaceutically acceptable salt thereof. CL075(3M002) is a thiazoloquinolinone derivative that stimulates TLR8 in human peripheral blood mononuclear cells. It activates NF-. kappa.B and preferentially triggers the production of TNF-. alpha.and IL-12. CL075 also induces secretion of IFN- α by TLR7, but to a lesser extent. It induced NF-. kappa.B activation at 0.4. mu.M (0.1. mu.g/ml) in TLR 8-transfected HEK293 cells, whereas about 10-fold more CL075 was required for NF-. kappa.B activation in TLR 7-transfected HEK293 cells.
In certain embodiments, the innate immune response activator is MEDI9197, or a pharmaceutically acceptable salt thereof. MEDI9197(3M052) is an injectable TLR7 and TLR8 agonist. It is an imidazoquinoline Immune Response Modifier (IRM) with a C18 lipid moiety and is designed for slow dissemination from the site of application.
In certain embodiments, the innate immune response activator is resiquimod (R848), or a pharmaceutically acceptable salt thereof. In particular, resiquimod is an agent that is useful as an immune response modifier and has antiviral and antitumor activity. It is used as a topical gel in the treatment of skin lesions such as those caused by herpes simplex virus and cutaneous T-cell lymphoma. It is also used as an adjuvant to improve the efficacy of vaccines. It has multiple action mechanisms, namely agonists of Toll-like receptors 7(TLR7) and 8(TLR8) and up-regulation of opioid growth factor receptors.
In certain embodiments, the innate immune response activator is TLR 7-selective amcanda (antidugs). In certain embodiments, the innate immune response activator is SM-324405, AZ12441970, or a pharmaceutically acceptable salt thereof.
In certain embodiments, the innate immune response activator is GS-9620. In certain embodiments, the innate immune response activator is PF-4878691. In certain embodiments, the activator of innate immune response is NKTR-262. In certain embodiments, the innate immune response activator is LHC 165.
In certain embodiments, the innate immune response activator is an inflammatory body inducer. Inflammasome is a multimeric protein complex that is essential for the host's defense against infection and endogenous danger signals. They promote the secretion of the proinflammatory cytokines Interleukin (IL) -1 β and IL-18 and cause a rapid and proinflammatory form of cell death called apoptosis.
In certain embodiments, the innate immune response activator is an NLRP3, AIM2, NLRC4, or NLRP1 inflammasome inducer.
In certain embodiments, the innate immune response activator is
Or a pharmaceutically acceptable salt thereof, wherein: r1Is H, R2Is H; r1Is a butyl radical, R2Is H; r1Is H, R2is-CO2CH3(ii) a Or R1Is a butyl radical, R2is-CO2CH3。
In certain embodiments, the innate immune response activator is imidazoquinoline (imidazonaphthyridine); imidazonaphthyridine; a pyrazolopyridine; aryl-substituted imidazoquinolines; a compound having a 1-alkoxy 1H-imidazole ring system; oxazolo [4,5-c ] -quinolin-4-amine; thiazolo [4,5-c ] -quinolin-4-amine; selenazolo [4,5-c ] -quinolin-4-amine; imidazonaphthyridine; imidazoquinoline amines; 1-substituted, 2-substituted 1H-imidazo [4,5-C ] quinolin-4-amines; fused cycloalkylimidazopyridines; 1H-imidazo [4,5-c ] quinolin-4-amine; 1-substituted 1H-imidazo- [4,5-c ] quinolin-4-amines; imidazo- [4,5-C ] quinolin-4-amine; 2-ethyl-1H-imidazo [4,5-c ] quinolin-4-amine; olefinic 1H-imidazo [4,5-c ] quinolin-4-amines; 6, 7-dihydro-8- (imidazo l-1-yl) -5-methyl-1-oxo-1H, 5H-benzo [ ij ] quinolizine-2-carboxylic acid; pyridoquinoxaline-6-carboxylic acid; 6, 7-dihydro-8- (imidazo l-1-yl) -5-methyl-1-oxo-1H, 5H-benzo [ ij ] quinolizine-2-carboxylic acid; substituted naphtho [ ij ] quinolizine; substituted pyridoquinoxaline-6-carboxylic acid; 7-hydroxy-benzo [ ij ] quinolizine-2-carboxylic acid derivatives; substituted benzo [ ij ] quinolizine-2-carboxylic acid; 7-hydroxy-benzo [ ij ] quinolizine-2-carboxylic acid; substituted pyrido [1,2,3, -de ] -1, 4-benzoxazines; an N-methylene malonate ester of tetrahydroquinoline, or a pharmaceutically acceptable salt thereof.
In certain embodiments, the innate immune response activator is any of the NLRP3 agonists disclosed in U.S. patent application u.s.s.n.15/253,215 filed on 31/8/2016, the entire contents of which are incorporated herein by reference.
In certain embodiments, the innate immune response activator is a ROR γ agonist. ROR γ agonists are agents that promote ROR γ activity, e.g., by binding and activating ROR γ or by increasing ROR γ expression in a patient or cell population. ROR γ agonists can be, for example, small organic molecules, polypeptides, or nucleic acids. Various ROR γ agonists are reported in the literature, such as those below: U.S. patent application n.14/398,774; zhang et al inmol pharmacol, (2012) vol.82, pages 583-590; and Wang et al inacs chem.biol. (2010), vol.5, pages 1029-1034; each of which is incorporated herein by reference.
In certain embodiments, the innate immune response activator is a ROR γ agonist, e.g.
And pharmaceutically acceptable salts thereof.
In certain embodiments, the innate immune response activator is a compound of formula (la) or a specific compound as described in U.S. patent application u.s.s.n.14/398,774:
or a pharmaceutically acceptable salt thereof; wherein:
A is aryl, aralkyl, heteroaryl, cycloalkyl, or heterocycloalkyl; each of which is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: halogen, hydroxy, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, -N (R)4)(R5)，—CO2R6，—C(O)R6，—CN，—C1-4alkylene-C1-4Alkoxy, -C1-4alkylene-N (R)4)(R5)，—C1-4alkylene-CO2R6，—O—C1-6alkylene-N (R)4)(R5)，—N(R4)C(O)—C1-6alkylene-N (R)4)(R5)，—S(O)pC1-6Alkyl, -SO2N(R4)(R5)，—N(R4)SO2(C1-6Alkyl) -, -C (O) N (R)4)(R5) and-N (R)4)C(O)N(R4)(R5)；
X is-O- (C (R)6)(R7)]—[C(R6)2]m-Ψ，—O—C(R6)2—C(R6)(R7)—C(R6)2-Ψ，—O—C(R6)2—C(R6)(R7)-Ψ，—C(R6)2—[C(R6)(R7)]—[C(R6)2]m-Ψ，—C(O)—[C(R6)(R7)]—[C(R6)2]m-Ψ，—C(R6)2—N(R8)—[C(R6)(R7)]—[C(R6)2]m-Ψ，—C(R6)═N-Ψ，—C(R6)2C(R6)═N-Ψ，—N═C(R6) - Ψ, or-N ═ C (R)6)C(R6)2- Ψ; wherein Ψ is a bond to the sulfonamide ring nitrogen atom in formula I;
y is-N (R)2)(R3) Or — O-aralkyl, wherein the aralkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: halogen, hydroxy, C1-6Alkoxy radical, C1-6Halogenoalkoxy, C1-6Alkyl radical, C1-6Haloalkyl, -N (R)4)(R5)，—CN，—CO2—C1-6Alkyl, -C (O) -C1-6Alkyl, -C (O) N (R)4)(R5)，—S(O)pC1-6Alkyl, -SO2N(R4)(R5) and-N (R)4)SO2(C1-6Alkyl groups);
R1independently in each case represents hydrogen, halogen, or C1-6An alkyl group;
R2is-C (O) -aryl, -C (O) -aralkyl, -C (O) - [ C (R) ]6)2]m-cycloalkyl, -C (O) - [ C (R) ]6)2]m-heterocyclyl, -C (O) -C1-6Alkyl, -C (O) -C1-6alkylene-C1-6Alkoxy, -C (O) -C1-6Alkylene-cycloalkyl, or-C (O) -C 1-6Alkylene-heterocycloalkyl; each of which is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: halogen, hydroxy, C1-6Alkoxy radical, C1-6Halogenoalkoxy, C1-6Alkyl radical, C1-6Haloalkyl, -N (R)4)(R5)，—CN，—CO2—C1-6Alkyl, -C (O) -C1-6Alkyl, -C (O) N (R)4)(R5)，—S(O)pC1-6Alkyl, -SO2N(R4)(R5) and-N (R)4)SO2(C1-6Alkyl groups);
R3is hydrogen or C1-6An alkyl group;
R4and R5Each independently of the other represents hydrogen or C1-6An alkyl group; or R4And R5Together with the nitrogen atom to which they are attached form a 3-7 membered heterocyclic ring;
R6in each case independently of one another represents hydrogen or C1-6An alkyl group;
R7is hydrogen, hydroxy, C1-6Hydroxyalkyl radical, C1-6Alkyl radical, C1-6Haloalkyl, -CO2R6，C1-6alkylene-CO2R6，C1-4Hydroxy alkylene-CO2R6，—N(R4)(R5)，C1-6alkylene-N (R)4)(R5)，C1-6hydroxyalkylene-N (R)4)(R5)，—N(R4)C(O)R9，C1-6alkylene-N (R)4)C(O)R9，C1-6alkylene-C (O) N (R)4)(R5)，—N(R4)CO2—C1-6Alkyl, or C1-6alkylene-N (R)4)(C(O)N(R4)(R5) (ii) a Or R7Is heterocycloalkyl or C1-4Alkylene-heterocycloalkyl, wherein heterocycloalkyl is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: oxo, halogen, hydroxy, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy, and C1-6A haloalkoxy group;
R8is hydrogen, C1-6Alkyl, or-C (O) -C1-6An alkyl group;
R9is hydrogen, C1-6Alkyl radical, C1-6Hydroxyalkyl radical, C1-6alkylene-N (R)4)(R5) Or C1-6alkylene-N (R) 4)C(O)—C1-6An alkyl group;
n is 1 or 2; and
m and p represent, independently of one another, 0, 1 or 2 for each case.
In certain embodiments, the innate immune response activator is any ROR γ agonist disclosed in U.S. patent application u.s.s.n.14/398,774 filed on 11/4/2014, which is incorporated herein by reference in its entirety. In certain embodiments, the innate immune response activator is any ROR γ agonist disclosed in U.S. patent application u.s.s.n.15/120,798 filed on 23/8/2016, the entire contents of which are incorporated herein by reference.
In certain embodiments, the innate immune response activator is a RIG-I like receptor (RLR) agonist. In certain embodiments, the innate immune response activator is RGT-100.
Cytokine
Drug delivery compositions and devices may comprise cytokines. Cytokines are a broad class of small proteins (-5-20 kDa) important in cell signaling. Their release has an effect on the behavior of the cells around them. Cytokines are involved in autocrine signaling, paracrine signaling, and endocrine signaling as immunomodulators. Cytokines include chemokines, interferons, interleukins, lymphokines, and tumor necrosis factors. Cytokines are produced by a variety of cells, including immune cells such as macrophages, B lymphocytes, T lymphocytes and mast cells, as well as endothelial cells, fibroblasts and various stromal cells. They act through receptors and play an important role in the immune system. Cytokines regulate a balance between humoral and cellular-based immune responses, and they regulate the maturation, growth and responsiveness of specific cell populations. Some cytokines enhance or inhibit the action of other cytokines in a complex manner. Cytokines are important in host responses to infection, immune responses, inflammation, trauma, sepsis, cancer and reproduction.
In addition, it is currently known in the art that the problems associated with delivery methods, administration and scheduling, and toxicity must be addressed in order to take full advantage of the immunostimulatory functions of various cytokines and chemokines.
In certain embodiments, the cytokine is IL-1, IL-1 α, IL-1 β, IL-2, IL-2 superakine, IL-6, IL-7, IL-9, AM0010, IL-12, IL-15, IL-15 superagonist, ALT-803, NIZ985, IL-16, IL-18, IL-21, IL-21 superagonist, denicorm, IL-21 superagonist antibody, IFN- α, IFN- β, IFN- γ, TNF- α, GM-CSF, cytokine fusion RG, 7461, RG7813, M9241, NKTR-214, NKTR-255, BMS-982470, BG-00001, 3L, or CDX-301.
In certain embodiments, the cytokine is ALT-803, NIZ985, denicotine, RG7461, RG7813, M9241, IFN- α, IFN- β, or IFN- γ.
In certain embodiments, the cytokine is an IL-15 superagonist or IL-21. In certain embodiments, the cytokine is an IL-15 superagonist.
In certain embodiments, the cytokine is an IL-15 superagonist, IL-21, IFN- α, IFN- β, IFN- γ, CCL4, CCL5, CXCL9, or
IL-15 (interleukin 15) is a cytokine structurally similar to IL-2, which is secreted by mononuclear phagocytes following viral infection. IL-15 induces cell proliferation of natural killer cells, the primary role of which is to kill cells infected with the virus. The binding of IL-15 to soluble IL-15 Ra produces a complex termed IL-15 superagonist (IL-15sa) that has greater biological activity than IL-15 alone. IL-15sa is an anti-tumor and anti-viral agent because of its ability to selectively expand NK and memory CD8+ T (mCD8+ T) lymphocytes.
In certain embodiments, the cytokine is an IL-15 superagonist known as ALT-803, an IL-15 superagonist. ALT-803 is thought to be a receptor that induces proliferation of memory CD8+ T cells, upregulates residual innate immunity, secretes interferon-gamma, and acquires the ability to kill malignant cells under conditions of antigen stimulation. Thus, ALT-803 may promote the expansion and activation of memory CD8+ T cells, while converting them into innate immune effector cells that exhibit potent antineoplastic activity. ALT-803 is a fusion protein of an IL-15 mutant and an IL-15R α/Fc complex, which has recently entered clinical trials as a direct immunomodulator. ALT-803 showed > 25-fold enhanced biological activity compared to IL-15.
In certain embodiments, the cytokine is NIZ985 (hetIL-15). Studies have shown that hetIL-15 administration promotes tumor infiltration and increased persistence of CD8+ T cells (including tumor-specific T cells) and results in an increased CD8+/Treg ratio. CD8+ T cells resident in tumors are characterized by effector cells characterized by increased proliferation (Ki67+) and high cytotoxic potential (Granzyme B +). In the absence of hetIL-15, the smaller tumor infiltrating T cell population showed high levels of the depletion marker PD-1, which may limit its anti-cancer effects. Provision of hetIL-15 resulted in a significant reduction in lymphocyte expression of PD-1, thereby alleviating one potential mechanism for the exhausted phenotype. Preclinical cancer studies support the use of hetIL-15 in tumor immunotherapy approaches to promote the development of an anti-tumor response by supporting effectors rather than modulating cells.
In certain embodiments, the cytokine is interferon alpha (IFN-. alpha.). IFN-alpha proteins are produced by leukocytes. They are mainly involved in the innate immune response against viral infections.
In certain embodiments, the cytokine is interferon beta (IFN- β). IFN- β comprises proteins produced by fibroblasts and is involved in the innate immune response. IFN- β stimulates both macrophages and NK cells to elicit an antiviral response, and is also active against tumors. In mice, IFN- β inhibits the production of growth factors by immune cells, thereby slowing tumor growth, and inhibits the production of growth factors by other cells, thereby blocking tumor angiogenesis and preventing the tumor from connecting to the vascular system.
In certain embodiments, the cytokine is interferon gamma (IFN-. gamma.). IFN-gamma, or type II interferon, which are cytokines useful for innate and adaptive immunity. IFN-gamma is an important macrophage activator and inducer of class II Major Histocompatibility Complex (MHC) molecule expression. Intensive in vitro studies of IFN- γ in cancer cells have been carried out and the results suggest that the antiproliferative activity of IFN- γ leads to growth arrest or cell death, which is usually apoptosis-induced, but sometimes also by autophagy. Clinical administration of IFN- γ has resulted in improved survival of patients with ovarian, bladder and melanoma cancers.
In certain embodiments, the cytokine is a chemokine. Chemokines are a family of small cytokines. The main role of chemokines is to act as chemoattractants to guide cell migration. Some chemokines control the immune system of cells during immune surveillance, such as directing lymphocytes into lymph nodes to enable screening for pathogen invasion by interacting with antigen presenting cells resident in these tissues. These are called homeostatic chemokines and their production and secretion does not require any stimulation of the cell from which they are derived. Some chemokines play a role in development, promoting angiogenesis (the growth of new blood vessels), or directing cells to tissues that provide specific signals critical to cell maturation. Other chemokines are inflammatory and released from a variety of cells in response to bacteria, viruses, or agents that cause physical damage (such as silica or urate crystals that occur in gout). Its release is usually stimulated by proinflammatory cytokines (e.g., interleukin 1). The primary function of inflammatory chemokines is to act as chemoattractants for leukocytes, recruiting monocytes, neutrophils, and other effector cells from the blood to the site of infection or tissue damage. Certain inflammatory chemokines activate cells to initiate an immune response or promote wound healing. They are released by many different cell types and are used to direct cells of both the innate and adaptive immune systems.
In addition, it is currently known in the art that the problems associated with delivery methods, administration and scheduling, and toxicity must be addressed to enable the immune stimulatory function of many chemokines to be fully exploited.
In certain embodiments, the chemokine is CCL1, CCL2, CCL3, CCL4, CCL5, CCL17, CCL19, CCL21, CCL22, CXCL9, CXCL10, CXCL11, CXCL13, CXCL16, or CX3CL 1.
Adaptive immune response activator
The drug delivery compositions and devices may comprise one or more adaptive immune response activators.
The adaptive immune response system, also known as the adaptive immune system, is a subsystem of the overall immune system that includes highly specialized systemic cells and processes that eliminate or prevent pathogen growth. The adaptive immune system is one of two major immune strategies found in vertebrates (the other being the innate immune system). Adaptive immunity produces immunological memory following an initial response to a particular pathogen and results in an enhanced response upon subsequent encounter with that pathogen. This adaptive immunization process is the basis for vaccination. Like the innate system, the adaptive system includes a humoral immune component and a cell-mediated immune component. Unlike the innate immune system, the adaptive immune system is highly specific for a particular pathogen.
When a pathogen evades the innate immune response system, the adaptive immune response system is triggered in the vertebrate, producing a threshold level of antigen, and producing a "strange" or "dangerous" signal that activates dendritic cells. The primary function of the adaptive immune system involves the recognition of specific "non-self antigens in the presence of" self during antigen presentation. Generating a response aimed at eliminating a particular pathogen or pathogen-infected cells; immunological memory is developed in which pathogens are "remembered" by memory B cells and memory T cells.
Useful methods of activating the adaptive immune response system (e.g., activating a therapeutic anti-tumor immunity) include blocking immune checkpoints. Immune checkpoints refer to a variety of inhibitory pathways that are hard-wired to the immune system and are critical to maintaining self-tolerance and modulating the duration and magnitude of physiological immune responses in peripheral tissues to minimize collateral tissue damage. Tumors select certain immune checkpoint pathways as the primary mechanism of immune resistance, particularly for T cells specific for tumor antigens. Because many immune checkpoints are triggered by ligand-receptor interactions, they are easily blocked by antibodies or modulated by ligand or receptor recombination. Cytotoxic T lymphocyte-associated antigen 4(CTLA-4) antibodies were the first such immunotherapeutic drug to receive FDA approval (leprimumab). Preliminary clinical findings using blockers of other immune checkpoint proteins, such as programmed cell death protein 1(PD-1), suggest that a wide and diverse opportunity to enhance anti-tumor immunity has the potential to generate a persistent clinical response.
PD-1, as an immune checkpoint, plays an important role in down-regulating the immune system by preventing T cell activation, in turn reducing autoimmunity and promoting self-tolerance. The inhibition of PD-1 is achieved by a dual mechanism of promoting apoptosis (programmed cell death) in antigen-specific T cells in lymph nodes while reducing apoptosis in regulatory T cells (suppressor T cells). A novel therapeutic agent that blocks PD-1, a PD-1 inhibitor (e.g., an anti-PD-1 antibody), activates the immune system to attack tumors and is therefore useful in the treatment of some types of cancer. Furthermore, the effect of antibodies to programmed death ligand 1(PD-L1) on the activation of an adaptive immune response is similar to antibodies targeting PD-1. Thus, it is expected that compositions and devices comprising anti-PD-L1 antibodies will provide similar therapeutic effects as compositions comprising anti-PD-1 antibodies.
In certain embodiments, the activator of an adaptive immune response is a small molecule. In certain embodiments, the activator of an adaptive immune response is a biological agent. In certain embodiments, the biological agent is a protein. In certain embodiments, the biological agent is an antibody or fragment thereof. In certain embodiments, the biological agent is a nucleic acid encoding a protein.
In certain embodiments, the activator of an adaptive immune response is an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-TIM 3 antibody, an anti-OX 40 antibody, an anti-GITR antibody, an anti-LAG-3 antibody, an anti-CD 137 antibody, an anti-CD 3 antibody, an anti-CD 27 antibody, an anti-CD 28 antibody, an anti-CD 28H antibody, an anti-CD 30 antibody, an anti-CD 39 antibody, an anti-CD 40 antibody, an anti-CD 43 antibody, an anti-CD 47 antibody, an anti-CD 48 antibody, an anti-CD 70 antibody, an anti-CD 73 antibody, an anti-CD 96 antibody, an anti-CD 123 antibody, an anti-CD 155 antibody, an anti-CD 160 antibody, an anti-CD 200 antibody, an anti-CD 244 antibody, an anti-ICOS antibody, an anti-TNFRSF 25 antibody, an anti-igd 2 antibody, an anti-DNAM 1 antibody, an anti-BTLA antibody, an anti-TIGIT antibody, an anti-GAL 1 antibody, an anti-gilec 1 antibody, an anti-gcbuthin 1 antibody, an anti-gchbn 1 antibody, an anti-tglec 1 antibody, an anti-gchbn 1 antibody, an anti-tg, anti-B7-H5 antibody, anti-B7-H6 antibody, anti-KIR antibody, anti-LIR antibody, anti-ILT antibody, anti-CEACAM 1 antibody, anti-CEACAM 5 antibody, anti-CEACAM 6 antibody, anti-MICA antibody, anti-MICB antibody, anti-NKG 2D antibody, anti-NKG 2A antibody, anti-A2 AR antibody, anti-C5 aR antibody, anti-TGF β R antibody, anti-CXCR 4 antibody, anti-CXCL 12 antibody, anti-CCL 2 antibody, anti-IL-10 antibody, anti-IL-13 antibody, anti-IL-23 antibody, anti-phosphatidylserine antibody, anti-neuropilin antibody, anti-GalCer antibody, anti-HER 2 antibody, anti-VEGFA antibody, anti-VEGFR antibody, anti-EGFR antibody, anti-Tie 2 antibody, anti-TRAIL-DR 4 or anti-TRAIL-DR 5 antibody.
In certain embodiments, the activator of an adaptive immune response is a fragment of any of the antibodies listed above. In certain embodiments, the activator of an adaptive immune response is a humanized form of any of the antibodies listed above. In certain embodiments, the activator of an adaptive immune response is a single chain of any of the antibodies listed above. In certain embodiments, the activator of an immune response is a multimeric form of any of the antibodies listed above (e.g., a dimeric IgA molecule, a pentavalent IgM molecule).
In certain embodiments, the activator of an adaptive immune response is an anti-PD-1 antibody, an agonist anti-CD 137 antibody, an
In certain embodiments, the adaptive immune response activator is pembrolizumab, nivolumab, pidilizumab, yipimima, tremelimumab, durvalumab, atelizumab, avelizumab, PF-06801591, utolizumab, PDR001, PBF-509, MGB453, LAG525, AMP-224, INCSFR 1210, INCANG 1876, INCANG 1949, samalizumab, PF-05082566, urelizumab, lilizumab, lulumab, BMS-936559, BMS-936561, BMS-986004, BMS-986012, BMS-986016, BMS-986178, IMP321, IPH2101, IPH2201, IPH5401, IPH4102, IPH4301, IPH52, IPH53, vailumUMEN, BME 0676, CG15080, CG15017, CGEGH 15080, CGMILDH 15080, CGEGMCIA NO-6035, CGTCK-15080, CGMCIA-6035, CGMCIA-35, CGTCK-15048, CGMCIA-35, CGTCK-35, CG15080, CGMCIA-NO-35, CGTCK-33, CGNO-35, CGMCIA-NO-35, CGNO-NO-3, CGNO-NO-35, CGNO-NO-80, CGNO-NO-3, CGNO-NO-80, CGNO-NO-80, CGNO-NO, pertuzumab, obinutuzumab, cabiralizumab, margetuximab, enobilituzumab, mogamulizumab, panitumumab, carlumab, ramucirumab, bevacizumab, rituximab, cetuximab, fresolimumab, dinolizumab, MGA012, AGEn1884, AGEn2034, LY3300054, JTX-4014, teplizumab, FPA150, PF-04136309, PF-06747143, AZD5069, GSK3359609, FAZ053, TSR022, MBG453, REGN2810, REGN3767, MOXR0916, PF-04518600, RO7009789, BMS986156, GWN323, JTX-NKTR-214, GSK 31998, GSK 31993 a, NIS 317, BGB 793, or BGB-74A.
In certain embodiments, the adaptive immune response activator is pembrolizumab, nivolumab, pidilizumab, primima, tremelimumab, durvalumab, astuzumab, REGN2810, MGA012, age 1884, age 2034, LY3300054, JTX-4014, or avelumab.
In certain embodiments, the adaptive immune response activator is an antibody mimetic or an antibody fusion.
In certain embodiments, the adaptive immune response activator is a bispecific antibody. In certain embodiments, the bispecific antibody is RG7802 (an antibody targeting carcinoembryonic antigen (CEA) and CD3 receptor), RG7828 (a bispecific monoclonal antibody targeting CD20 on B cells and CD3 on T cells), RG7221 (a bispecific monoclonal antibody targeting VEGF and angiopoietin 2), RG7386 (a bispecific monoclonal antibody targeting FAP and DR 5), ERY974 (a bispecific monoclonal antibody targeting CD3 and glypican-3), MGD012 (a bispecific monoclonal antibody targeting PD-1 and LAG-3), AMG211 (a bispecific T cell conjugate targeting CD3 and CEA), MEDI573 (a bispecific monoclonal antibody targeting IGF1 and IGF 2), MEDI565 (a bispecific monoclonal antibody targeting CD3 and CEA), FS17 (unpublished target), FS18 (a monoclonal antibody targeting LAG3 and unpublished target), bispecific antibody 20 (unpublished target), FS22 (unpublished target), FS101 (bispecific monoclonal antibody targeting EGFR and HGF), FS117 (unpublished target), FS118 (bispecific monoclonal antibody targeting LAG3 and PD-L1), RO6958688 (bispecific monoclonal antibody targeting CD3 and CEA), MCLA-128 (bispecific monoclonal antibody targeting HER2 and HER 3), M7824 (bifunctional fusion protein targeting PD-L1 and TGF β), MGD009 (humanized antibody recognizing both B7-H3 and CD 3), or MGD013 (bispecific PD-1 and LAG-3 antibodies).
In certain embodiments, the adaptive immune response activator is an antibody-drug conjugate. In certain embodiments, the antibody-drug conjugate is trastuzumab emtansine, inotuzumab ozogamicin, PF-06647020, PF-06647263, PF-06650808, RG7596, RG7841, RG7882, RG7986, DS-8201, ABBV-399, glembatuzumab vedotin, inotuzumab ozogamicin, MEDI4276, or a pharmaceutically acceptable salt thereof.
In certain embodiments, the adaptive immune response activator is a small molecule. In certain embodiments, the small molecule is an IDO inhibitor, a TGF β R inhibitor, a BRAF inhibitor, a KIT inhibitor, an A2aR inhibitor, a Tie2 inhibitor, an arginase inhibitor, an iNOS inhibitor, a HIF1 α inhibitor, a STAT3 inhibitor, a PGE2 inhibitor, a PDE5 inhibitor, a RON inhibitor, an mTOR inhibitor, a JAK2 inhibitor, an HSP90 inhibitor, a PI3K-AKT inhibitor, a β -catenin inhibitor, a GSK3 β inhibitor, an IAP inhibitor, an HDAC inhibitor, a DNMT inhibitor, a BET inhibitor, a COX2 inhibitor, a PDGFR inhibitor, a VEGFR-ABL inhibitor, a proteasome inhibitor, an angiogenesis inhibitor, a MEK inhibitor, a BRAF + MEK inhibitor, a pan-RAF inhibitor, an EGFR inhibitor, a PARP inhibitor, a glutaminase inhibitor, a WNT inhibitor, a FAK inhibitor, an ALK inhibitor, a CDK4/6 inhibitor, or an FGFR3 inhibitor.
In certain embodiments, the small molecule is celecoxib, sunitinib, imatinib, vemurafenib, dabrafenib, bortezomib, vorinostat, pomalidomide, thalidomide, lenalidomide, epacadostat, indoximid, GDC0919, BMS986205, AZD8055, AZD4635, CPI-444, PBF509, LCL161, CB-839, CB-1158, FPA008, BLZ945, IPI-549, pexidartinib, galininisertib, birinapag, trimitinib, cobicistinib, binimetinib, ensaritib, gefitinib, pazopanib, sorafenib, ninidanib, SYM004, veliparib, olaparib, BGB-290, Iverivib 919155, azacitib, azacitidine, Sizotinib, Ruxitabine, Ruxifragilis-3, SRAdrianib, SRIxatilib, Rutacrolib-366335, Rutacrolimus, Rutacalcinib, Rutacalciib, Rutacalcinib, SRI-366326, Rutacrolimus, Rutacrolib, Rutacrolimus, Rutacalcib, Rutacalciib, Rutacalcinib, Rutacrolib, Rutacrolimus, Rutacrolib, Rutac, WNT974, BGJ398, LY2874455, or a pharmaceutically acceptable salt thereof.
Other therapeutic agents
Drug delivery compositions and devices may contain other therapeutic agents.
In certain embodiments, the drug delivery compositions and devices may comprise modulators of macrophage effector function. Macrophages are immune cells derived from circulating monocytes, reside in all tissues, and are involved in many pathological states. Macrophages have two widely divergent roles in cancer, which can promote tumor growth, but can also serve as important immune effectors for therapeutic antibodies. Macrophages express all types of Fc γ receptors, which have the potential to destroy tumors by antibody-dependent cellular phagocytosis. Many studies have shown that macrophage phagocytosis is the primary mechanism of action of many antibodies approved for the treatment of cancer. Accordingly, various methods of enhancing macrophage response to therapeutic antibodies are being investigated, including the search for new targets and the development of antibodies with enhanced function. Macrophage response to antibody therapy can also be enhanced by engineered Fc variants, bispecific antibodies or antibody-drug conjugates. Macrophages have shown success as effectors of cancer immunotherapy.
In certain embodiments, the modulator of macrophage effector function is a modulator of suppressor bone marrow cells, including myeloid-derived suppressor cells (MDSCs). In certain embodiments, the macrophage effector function modulator can kill, deplete or enhance macrophages and/or MDSCs. In certain embodiments, the modulator of macrophage effector function is an anti-CD 40 antibody, an anti-CD 47 antibody, an anti-CSF 1 antibody, or an anti-CSF 1R antibody. In certain embodiments, the modulator of macrophage effector function is SRF231, Hu5F9-G4, CC-900002, or TTI-621 (anti-CD 47 antibody). In certain embodiments, the modulator of macrophage effector function is MCS-110 (anti-CSF 1 antibody). In certain embodiments, the modulator of macrophage effector function is FPA008, RG7155, IMC-CS4, AMG820, or UCB6352 (anti-CSF 1R antibody). In certain embodiments, the macrophage effector function modulator is a small molecule inhibitor of CSF 1R. In certain embodiments, the macrophage effector function modulator is BLZ945, GW2580, or PLX3397 (a small molecule inhibitor of CSF 1R). In certain embodiments, the macrophage effector function modulator is a BTK inhibitor, an ITK inhibitor, a PI3K γ inhibitor, or a PI3K inhibitor. In certain embodiments, a modulator of macrophage effector function may replace one or more activators of adaptive immune response in a composition or device.
In certain embodiments, the drug delivery compositions and devices may further comprise an oncogenic virus. In certain embodiments, the tumorigenic virus includes, but is not limited to, herpes simplex virus (e.g., HSV1716, OncoVex GM-CSF); adenoviruses (e.g., H101, Onyx-15); poliovirus (e.g., PV1 (RIPO)); reovirus (e.g., reolysin); senecavir (e.g., NTX-010, SVV-001); a Rigvir virus; maraba virus; measles; a newcastle virus; vaccinia; or ECHO virus.
In certain embodiments, the drug delivery compositions and devices may further comprise a radioisotope (e.g., as part of a molecule or on a bead). In certain embodiments, the radioisotope is yttrium-90, palladium-103, iodine-125, cesium 131, or iridium 192.
In certain embodiments, the drug delivery compositions and devices may further comprise a chemotherapeutic agent. In certain embodiments, chemotherapeutic agents include, but are not limited to, antiestrogens (e.g., tamoxifen, raloxifene, and megestrol), LHRH agonists (e.g., goscrlin and leuprolide), antiandrogens (e.g., flutamide and bicalutamide), photodynamic therapy (e.g., verteporfin (BPD-MA), phthalocyanines, photosensitizer Pc4, and demethoxy-hypocrellin A (2BA-2-DMHA)), nitrogen mustards (e.g., cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas (e.g., carmustine (BCNU) and lomustine (CCNU)), alkylsulfonates (e.g., leucinolone (Leukob), and/or another), and combinations thereof Desman and troosulfan), triazenes (e.g., dacarbazine and temozolomide), platinum-containing compounds (e.g., cisplatin, carboplatin, and oxaliplatin), vinca alkaloids (e.g., vincristine, vinblastine, vindesine, and vinorelbine), taxanes (e.g., paclitaxel or paclitaxel equivalents, such as nanoparticulate albumin-bound paclitaxel (ABRAXANE), docosahexaenoic acid-bound paclitaxel (DHA-paclitaxel, Taxoprexin), polyglutamate-bound paclitaxel (PG-paclitaxel, polyglutamate-paclitaxel, CT-2103, XYOTAX), tumor-activated prodrug (TAP) ANG1005 (Angiopep-2 bound to three paclitaxel molecules), paclitaxel-EC-1 (paclitaxel bound to peptide EC-1 recognizing erbB 2), and glucose-conjugated paclitaxel, e.g., 2' -methyl 2-glucopyranosylsuccinate; docetaxel, taxol), epidophyllins (e.g., etoposide phosphate, teniposide, topotecan, 9-aminocamptothecin, camptotorinoecan, irinotecan, crisnatol, and mitomycin C), antimetabolites, DHFR inhibitors (e.g., methotrexate, trimetrexate, and edatrexate), IMP dehydrogenase inhibitors (e.g., mycophenolic acid, tiazofurin, ribavirin, and EICAR), ribonucleic acid reductase inhibitors (e.g., hydroxyurea and deferoxamine), uracil analogs (e.g., 5-fluorouracil (5-FU), floxuridine, doxifluridine, lacitrexed, tegafur, and capecitabine), cytosine analogs (e.g., cytarabine (ara C), cytarabine, and fludarabine), purine analogs (e.g., mercaptopurine and thioguanine), vitamin D3 analogs (e.g., 1089, CB 1093 and KH1060), prenylation inhibitors (e.g., lovastatin), dopaminergic neurotoxins (e.g., 1-methyl) -4-phenylpyridinium ion), cell cycle inhibitors (e.g., staurosporine), actinomycins (e.g., actinomycin D, dactinomycin), bleomycin (e.g., bleomycin A2, bleomycin B2, and duomycin), anthracyclines (e.g., daunorubicin, doxorubicin, PEGylated liposomal doxorubicin, idarubicin, epirubicin, pirarubicin, daunorubicin, and mitoxantrone), MDR inhibitors (e.g., verapamil), Ca 2+Inhibitors of ATPase (e.g. thapsigargin), orlistatRaw, gemcitabine, carmichycin, folinic acid, pemetrexed, cyclophosphamide, dacarbazine, procarbazine, prednisolone, dexamethasone, camptothecin, plicamycin, asparaginase, aminopterin, methotrexate, porphyrinomycin, melphalan, vincristine, vinblastine epoxide, chlorambucil, trebestine, procarbazine, discodermolide, carminomycin, aminopterin, hexamethylmelamine, and pharmaceutically acceptable salts thereof.
In certain embodiments, the chemotherapeutic agent is an immunomodulatory chemotherapeutic agent. In certain embodiments, the chemotherapeutic agent has a known immunomodulatory function (e.g., induces immunogenic cell death or depletes immunosuppressive regulatory immune cells). In certain embodiments, chemotherapeutic agents are included in drug delivery compositions and devices due to their immunotherapeutic properties rather than their use as conventional cancer cell intrinsic cytotoxic chemotherapy. In certain embodiments, the drug delivery compositions and devices are free of chemotherapeutic agents. In certain embodiments, the drug delivery compositions and devices are free of cytotoxic agents.
In certain embodiments, the drug delivery compositions and devices may further comprise a targeting agent. In certain embodiments, the targeting agent includes, but is not limited to, an IDO inhibitor, a TGF β R inhibitor, an arginase inhibitor, an iNOS inhibitor, a HIF1 α inhibitor, a STAT3 inhibitor, a CSF1R inhibitor, a PGE2 inhibitor, a PDE5 inhibitor, a RON inhibitor, an mTOR inhibitor, a JAK2 inhibitor, a HSP90 inhibitor, a PI3K-AKT inhibitor, a β -catenin inhibitor, a GSK3 β inhibitor, an IAP inhibitor, an HDAC inhibitor, a DNMT inhibitor, a BET inhibitor, A2AR inhibitor, a BRAF + MEK inhibitor, a pan-RAF inhibitor, a PI3K γ inhibitor, a PI3K inhibitor, an EGFR inhibitor, a VEGF inhibitor, a PARP inhibitor, a glutaminase inhibitor, a BTK inhibitor, an ITK inhibitor, a WNT inhibitor, a FAK inhibitor, an ALK inhibitor, a CDK4/6 inhibitor, a or FGFR3 inhibitor.
In certain embodiments, the targeting agent includes, but is not limited to, imatinib, thalidomide, lenalidomide, tyrosine kinase inhibitors (e.g., axitinib (AG013736), bosutinib (SKI-606), cediranib (R)ECENTINTM, AZD2171), dasatinib (b)BMS-354825), erlotinib
Embodiments of drug delivery compositions and devices
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel and a proinflammatory pathway inhibitor.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel, a proinflammatory pathway inhibitor, and an innate immune response activator.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel, a proinflammatory pathway inhibitor, an innate immune response activator, and other innate immune response activators.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel, a proinflammatory pathway inhibitor, an innate immune response activator, and a cytokine.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel, a proinflammatory pathway inhibitor, an innate immune response activator, other innate immune response activators, and a cytokine.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel, a proinflammatory pathway inhibitor, an innate immune response activator, and a chemokine.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel, a proinflammatory pathway inhibitor, an innate immune response activator, other innate immune response activators, and a chemokine.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel, a proinflammatory pathway inhibitor, and a cytokine.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel, a proinflammatory pathway inhibitor, and a chemokine.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel, a proinflammatory pathway inhibitor, and an adaptive immune response activator.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel, a proinflammatory pathway inhibitor, an innate immune response activator, and an adaptive immune response activator.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel, a proinflammatory pathway inhibitor, an innate immune response activator, other innate immune response activators, and an adaptive immune response activator.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel, a proinflammatory pathway inhibitor, an adaptive immune response activator, and other adaptive immune response activators.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel, a proinflammatory pathway inhibitor, an adaptive immune response activator, and two other adaptive immune response activators.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel, a proinflammatory pathway inhibitor, an innate immune response activator, a cytokine, and an adaptive immune response activator.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel, a proinflammatory pathway inhibitor, an innate immune response activator, other innate immune response activators, cytokines, and an adaptive immune response activator.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel, a proinflammatory pathway inhibitor, an innate immune response activator, a cytokine, an adaptive immune response activator, and other adaptive immune response activators.
In certain embodiments, the drug delivery compositions and devices comprise hydrogels, pro-inflammatory pathway inhibitors, innate immune response activators, other innate immune response activators, cytokines, adaptive immune response activators, and other adaptive immune response activators.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel, a proinflammatory pathway inhibitor, an innate immune response activator, a chemokine, and an adaptive immune response activator.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel, a proinflammatory pathway inhibitor, an innate immune response activator, other innate immune response activators, a chemokine, and an adaptive immune response activator.
In certain embodiments, the drug delivery compositions and devices comprise hydrogels, pro-inflammatory pathway inhibitors, innate immune response activators, chemokines, adaptive immune response activators, and other adaptive immune response activators.
In certain embodiments, the drug delivery compositions and devices comprise hydrogels, pro-inflammatory pathway inhibitors, innate immune response activators, other innate immune response activators, chemokines, adaptive immune response activators, and other adaptive immune response activators.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel, a proinflammatory pathway inhibitor, a cytokine, and an adaptive immune response activator.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel, a proinflammatory pathway inhibitor, a cytokine, an adaptive immune response activator, and other adaptive immune response activators.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel, a proinflammatory pathway inhibitor, a chemokine, and an adaptive immune response activator.
In certain embodiments, the drug delivery compositions and devices comprise hydrogels, pro-inflammatory pathway inhibitors, chemokines, adaptive immune response activators, and other adaptive immune response activators.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel and an anti-IL-1 β antibody.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel and an anti-IL-6 antibody.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel and an anti-IL-6R antibody.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel and an inhibitor of a pro-inflammatory immune response mediated by the p38 mitogen-activated protein kinase (MAPK) pathway.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel and a p38 MAPK inhibitor.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel and a p38 a/β MAPK inhibitor that binds to an allosteric binding site of ATP and/or p38 MAPK.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel and a loshapimod.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel and a TGF β R inhibitor.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel and a CCR2 inhibitor.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel and a CXCR4 inhibitor.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel, an anti-IL-1 β antibody, and an interferon gene Stimulator (STING) agonist.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel, an anti-IL-6 antibody, and an interferon gene Stimulator (STING) agonist.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel, an anti-IL-6R antibody, and an interferon gene Stimulator (STING) agonist.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel, a TGF β R inhibitor, and an interferon gene Stimulator (STING) agonist.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel, a CCR2 inhibitor, and an interferon gene Stimulator (STING) agonist.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel, a CXCR4 inhibitor, and an interferon gene Stimulator (STING) agonist.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel, an inhibitor of a pro-inflammatory immune response mediated by the p38 mitogen-activated protein kinase (MAPK) pathway, and a TLR7/8 agonist.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel, a p38 MAPK inhibitor, and a TLR7/8 agonist.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel, a p38 a/β MAPK inhibitor that binds to an allosteric binding site of ATP and/or p38 MAPK, and a TLR7/8 agonist.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel, a loshapimod, and a TLR7/8 agonist.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel, an anti-IL-1 β antibody, and 2 '3' -cGAMP.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel, an anti-IL-6 antibody, and 2 '3' -cGAMP.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel, an anti-IL-6R antibody, and 2 '3' -cGAMP.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel, an anti-IL-1 β antibody, and 2 '3' -c-di-am (ps)2(Rp, Rp).
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel, an anti-IL-6 antibody, and 2 '3' -c-di-am (ps)2(Rp, Rp).
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel, an anti-IL-6R antibody, and 2 '3' -c-di-am (ps)2(Rp, Rp).
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel, an inhibitor of a pro-inflammatory immune response mediated by the p38 mitogen-activated protein kinase (MAPK) pathway, and resiquimod.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel, a p38 MAPK inhibitor, and resiquimod.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel, a p38 a/β MAPK inhibitor that binds to an allosteric binding site of ATP and/or p38 MAPK, and resiquimod.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel, a loshapimod, and resiquimod.
In certain embodiments, the drug delivery compositions and devices comprise a hydrogel and resiquimod.
In certain embodiments, the drug delivery compositions and devices comprise hyaluronic acid and an anti-IL-1 β antibody.
In certain embodiments, the drug delivery compositions and devices comprise hyaluronic acid and an anti-IL-6 antibody.
In certain embodiments, the drug delivery compositions and devices comprise hyaluronic acid and an anti-IL-6R antibody.
In certain embodiments, the drug delivery compositions and devices comprise hyaluronic acid and an inhibitor of a pro-inflammatory immune response mediated by the p38 mitogen-activated protein kinase (MAPK) pathway.
In certain embodiments, the drug delivery compositions and devices comprise hyaluronic acid and a p38 MAPK inhibitor.
In certain embodiments, the drug delivery compositions and devices comprise hyaluronic acid and a p38 a/β MAPK inhibitor that binds to an allosteric binding site of ATP and/or p38 MAPK.
In certain embodiments, the drug delivery compositions and devices comprise hyaluronic acid and loshapimod.
In certain embodiments, the drug delivery compositions and devices comprise hyaluronic acid and a TGF β R inhibitor.
In certain embodiments, the drug delivery compositions and devices comprise hyaluronic acid and a CCR2 inhibitor.
In certain embodiments, the drug delivery compositions and devices comprise hyaluronic acid and a CXCR4 inhibitor.
In certain embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an anti-IL-1 β antibody, and an interferon gene Stimulator (STING) agonist.
In certain embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an anti-IL-6 antibody, and an interferon gene Stimulator (STING) agonist.
In certain embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an anti-IL-6R antibody, and an interferon gene Stimulator (STING) agonist.
In certain embodiments, the drug delivery compositions and devices comprise hyaluronic acid, a TGF β R inhibitor, and an interferon gene Stimulator (STING) agonist.
In certain embodiments, the drug delivery compositions and devices comprise hyaluronic acid, a CCR2 inhibitor, and an interferon gene Stimulator (STING) agonist.
In certain embodiments, the drug delivery compositions and devices comprise hyaluronic acid, a CXCR4 inhibitor, and an interferon gene Stimulator (STING) agonist.
In certain embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an inhibitor of a pro-inflammatory immune response mediated by the p38 mitogen-activated protein kinase (MAPK) pathway, and a TLR7/8 agonist.
In certain embodiments, the drug delivery compositions and devices comprise hyaluronic acid, a p38 MAPK inhibitor, and a TLR7/8 agonist.
In certain embodiments, the drug delivery compositions and devices comprise hyaluronic acid, a p38 a/β MAPK inhibitor that binds to an allosteric binding site of ATP and/or p38 MAPK, and a TLR7/8 agonist.
In certain embodiments, the drug delivery compositions and devices comprise hyaluronic acid, loshapimod, and a TLR7/8 agonist.
In certain embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an anti-IL-1 β antibody, and 2 '3' -cGAMP.
In certain embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an anti-IL-6 antibody, and 2 '3' -cGAMP.
In certain embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an anti-IL-6R antibody, and 2 '3' -cGAMP.
In certain embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an anti-IL-1 β antibody, and 2 '3' -c-di-am (ps)2(Rp, Rp).
In certain embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an anti-IL-6 antibody, and 2 '3' -c-di-am (ps)2(Rp, Rp).
In certain embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an anti-IL-6R antibody, and 2 '3' -c-di-am (ps)2(Rp, Rp).
In certain embodiments, the drug delivery compositions and devices comprise hyaluronic acid, an inhibitor of a pro-inflammatory immune response mediated by the p38 mitogen-activated protein kinase (MAPK) pathway, and resiquimod.
In certain embodiments, the drug delivery compositions and devices comprise hyaluronic acid, a p38 MAPK inhibitor, and resiquimod.
In certain embodiments, the drug delivery compositions and devices comprise hyaluronic acid, a p38 a/β MAPK inhibitor that binds to an allosteric binding site of ATP and/or p38 MAPK, and resiquimod.
In certain embodiments, the drug delivery compositions and devices comprise hyaluronic acid, loshapimod, and resiquimod.
In certain embodiments, the drug delivery compositions and devices comprise hyaluronic acid and resiquimod.
In certain embodiments, the drug delivery compositions and devices comprise alginate and anti-IL-1 β antibodies.
In certain embodiments, the drug delivery compositions and devices comprise alginate and an anti-IL-6 antibody.
In certain embodiments, the drug delivery compositions and devices comprise alginate and an anti-IL-6R antibody.
In certain embodiments, the drug delivery compositions and devices comprise alginate and an inhibitor of the pro-inflammatory immune response mediated by the p38 mitogen-activated protein kinase (MAPK) pathway.
In certain embodiments, the drug delivery compositions and devices comprise alginate and a p38 MAPK inhibitor.
In certain embodiments, the drug delivery compositions and devices comprise alginate and a p38 a/β MAPK inhibitor that binds to the allosteric binding site of ATP and/or p38 MAPK.
In certain embodiments, the drug delivery compositions and devices comprise alginate and loshapimod.
In certain embodiments, the drug delivery compositions and devices comprise alginate, anti-IL-1 β antibodies, and interferon gene Stimulator (STING) agonists.
In certain embodiments, the drug delivery compositions and devices comprise alginate, anti-IL-6 antibodies, and interferon gene Stimulator (STING) agonists.
In certain embodiments, the drug delivery compositions and devices comprise alginate, anti-IL-6R antibodies, and interferon gene Stimulator (STING) agonists.
In certain embodiments, the drug delivery compositions and devices comprise alginate, an inhibitor of pro-inflammatory immune response mediated by the p38 mitogen-activated protein kinase (MAPK) pathway, and a TLR7/8 agonist.
In certain embodiments, the drug delivery compositions and devices comprise alginate, a p38 MAPK inhibitor, and a TLR7/8 agonist.
In certain embodiments, drug delivery compositions and devices comprise alginate, a p38 a/β MAPK inhibitor that binds to an allosteric binding site of ATP and/or a p38 MAPK, and a TLR7/8 agonist.
In certain embodiments, the drug delivery compositions and devices comprise alginate, loshapimod, and a TLR7/8 agonist.
In certain embodiments, the drug delivery compositions and devices comprise alginate, an anti-IL-1 β antibody, and 2 '3' -cGAMP.
In certain embodiments, the drug delivery compositions and devices comprise alginate, an anti-IL-6 antibody, and 2 '3' -cGAMP.
In certain embodiments, the drug delivery compositions and devices comprise alginate, an anti-IL-6R antibody, and 2 '3' -cGAMP.
In certain embodiments, the drug delivery compositions and devices comprise alginate, anti-IL-1 β antibodies, and 2 '3' -c-di-am (ps)2(Rp, Rp).
In certain embodiments, the drug delivery compositions and devices comprise alginate, anti-IL-6 antibodies, and 2 '3' -c-di-am (ps)2(Rp, Rp).
In certain embodiments, the drug delivery compositions and devices comprise alginate, anti-IL-6R antibodies, and 2 '3' -c-di-am (ps)2(Rp, Rp).
In certain embodiments, the drug delivery compositions and devices comprise alginate, an inhibitor of a pro-inflammatory immune response mediated by the p38 mitogen-activated protein kinase (MAPK) pathway, and resiquimod.
In certain embodiments, the drug delivery compositions and devices comprise alginate, a p38 MAPK inhibitor, and resiquimod.
In certain embodiments, the drug delivery compositions and devices comprise alginate, a p38 a/β MAPK inhibitor that binds to the allosteric binding site of ATP and/or p38 MAPK, and resiquimod.
In certain embodiments, the drug delivery compositions and devices comprise alginate, loshapimod, and resiquimod.
In certain embodiments, the drug delivery compositions and devices comprise alginate and resiquimod.
In certain embodiments, the drug delivery compositions and devices are free of alginate, COX-2 inhibitors (e.g., celecoxib), and anti-PD-1 antibodies.
In certain embodiments, the drug delivery compositions and devices are free of 1,3, -bis (2-chloroethyl) -1-nitrosourea (BCNU) and ethylene-vinyl acetate copolymer.
Drug delivery composition and device properties
Biomaterials useful in the drug delivery compositions and devices described herein are biocompatible. In some embodiments, the biomaterial (e.g., hydrogel) is biodegradable. Drug delivery compositions and devices are capable of chemical or biological degradation in a physiological environment, such as in vivo. Degradation of the composition and device can occur at different rates depending on the components and hydrogel used. For example, the half-life of the compositions and devices (the time for 50% of the composition to degrade into monomers and/or other non-polymeric moieties) may be on the order of days, weeks, months or years. The compositions and devices can be biodegraded, for example, by enzymatic activity or cellular mechanisms, in some cases, for example, by exposure to lysozyme (e.g., having a relatively low pH), or by simple hydrolysis. In some cases, compositions and devices can be broken down into monomeric and/or other non-polymeric moieties that can be reused or disposed of by the cells without significant toxic effects on the cells. The drug delivery compositions and devices are stable in vivo such that they deliver the drug to the intended target within an appropriate time.
In certain embodiments, less than or equal to 90%, less than or equal to 80%, less than or equal to 70%, less than or equal to 60%, less than or equal to 50%, less than or equal to 40%, less than or equal to 30%, less than or equal to 20%, less than or equal to 10%, less than or equal to 5%, less than or equal to 4%, less than or equal to 3%, less than or equal to 2%, less than or equal to 1%, less than or equal to 0.5%, or less than or equal to 0.1% of the devices remain in the body 12 months after administration (e.g., implantation) of the drug delivery composition or device.
In certain embodiments, less than or equal to 90%, less than or equal to 80%, less than or equal to 70%, less than or equal to 60%, less than or equal to 50%, less than or equal to 40%, less than or equal to 30%, less than or equal to 20%, less than or equal to 10%, less than or equal to 5%, less than or equal to 4%, less than or equal to 3%, less than or equal to 2%, less than or equal to 1%, less than or equal to 0.5%, or less than or equal to 0.1% of the composition remains in the
In certain embodiments, less than or equal to 90%, less than or equal to 80%, less than or equal to 70%, less than or equal to 60%, less than or equal to 50%, less than or equal to 40%, less than or equal to 30%, less than or equal to 20%, less than or equal to 10%, less than or equal to 5%, less than or equal to 4%, less than or equal to 3%, less than or equal to 2%, less than or equal to 1%, less than or equal to 0.5%, or less than or equal to 0.1% of the composition remains in the body 5 months after administration (e.g., implantation) of the drug delivery composition or device.
In certain embodiments, less than or equal to 90%, less than or equal to 80%, less than or equal to 70%, less than or equal to 60%, less than or equal to 50%, less than or equal to 40%, less than or equal to 30%, less than or equal to 20%, less than or equal to 10%, less than or equal to 5%, less than or equal to 4%, less than or equal to 3%, less than or equal to 2%, less than or equal to 1%, less than or equal to 0.5%, or less than or equal to 0.1% of the composition remains in the body for 4 months after administration (e.g., implantation) of the drug delivery composition or device.
In certain embodiments, less than or equal to 90%, less than or equal to 80%, less than or equal to 70%, less than or equal to 60%, less than or equal to 50%, less than or equal to 40%, less than or equal to 30%, less than or equal to 20%, less than or equal to 10%, less than or equal to 5%, less than or equal to 4%, less than or equal to 3%, less than or equal to 2%, less than or equal to 1%, less than or equal to 0.5%, or less than or equal to 0.1% of the composition remains in the body 3 months after administration (e.g., implantation) of the drug delivery composition or device.
In certain embodiments, less than or equal to 90%, less than or equal to 80%, less than or equal to 70%, less than or equal to 60%, less than or equal to 50%, less than or equal to 40%, less than or equal to 30%, less than or equal to 20%, less than or equal to 10%, less than or equal to 5%, less than or equal to 4%, less than or equal to 3%, less than or equal to 2%, less than or equal to 1%, less than or equal to 0.5%, or less than or equal to 0.1% of the composition remains in the body 2 months after administration (e.g., implantation) of the drug delivery composition or device.
In certain embodiments, less than or equal to 90%, less than or equal to 80%, less than or equal to 70%, less than or equal to 60%, less than or equal to 50%, less than or equal to 40%, less than or equal to 30%, less than or equal to 20%, less than or equal to 10%, less than or equal to 5%, less than or equal to 4%, less than or equal to 3%, less than or equal to 2%, less than or equal to 1%, less than or equal to 0.5%, or less than or equal to 0.1% of the composition remains in the body 1 month after administration (e.g., implantation) of the drug delivery composition or device.
In certain embodiments, less than or equal to 90%, less than or equal to 80%, less than or equal to 70%, less than or equal to 60%, less than or equal to 50%, less than or equal to 40%, less than or equal to 30%, less than or equal to 20%, less than or equal to 10%, less than or equal to 5%, less than or equal to 4%, less than or equal to 3%, less than or equal to 2%, less than or equal to 1%, less than or equal to 0.5%, or less than or equal to 0.1% of the composition remains in the body 1 week after administration (e.g., implantation) of the drug delivery composition or device.
In certain embodiments, less than or equal to 90%, less than or equal to 80%, less than or equal to 70%, less than or equal to 60%, less than or equal to 50%, less than or equal to 40%, less than or equal to 30%, less than or equal to 20%, less than or equal to 10%, less than or equal to 5%, less than or equal to 4%, less than or equal to 3%, less than or equal to 2%, less than or equal to 1%, less than or equal to 0.5%, or less than or equal to 0.1% of the composition remains in the body 1 day after administration (e.g., implantation) of the drug delivery composition or device.
The storage modulus in viscoelastic materials measures the amount of storage in the elastic portion of the material. Storage modulus can be measured with a rheometer. The measurements provided herein were performed at room temperature using a TA instruments AR-G2 electromagnetic bearing rheometer. The storage modulus of the drug delivery compositions and devices will vary based on the composition of the composition.
In general, storage modulus and thiol-modified hyaluronic acid (e.g.,
In certain embodiments, the drug delivery composition or device described herein has a storage modulus of at least 50Pa, at least 100Pa, at least 200Pa, at least 300Pa, at least 400Pa, at least 500Pa, at least 600Pa, at least 700Pa, at least 800Pa, at least 900Pa, at least 1000Pa, at least 1100Pa, at least 1200Pa, at least 1300Pa, at least 1400Pa, at least 1500Pa, at least 1600Pa, at least 1700Pa, at least 1800Pa, at least 1900Pa, at least 2000Pa, at least 2100Pa, at least 2200Pa, at least 2300Pa, at least 2400Pa, at least 2500Pa, at least 2600Pa, at least 2700Pa, at least 2800Pa, at least 2900Pa, or at least 3000 Pa.
In certain embodiments, the drug delivery compositions or devices described herein have a storage modulus of from about 50Pa to about 100,000,000Pa, from about 50Pa to about 100,000Pa, from about 50Pa to about 10,000Pa, from about 50Pa to about 3,000Pa, from about 100Pa to about 2,000Pa, from about 500Pa to about 3,000Pa, from about 500Pa to about 2,000Pa, from about 1,000Pa to about 2,000Pa, from about 1,200Pa to about 1,800Pa, from about 1,300Pa to about 1,700Pa, or from about 1,400Pa to about 1,600 Pa.
In certain embodiments, the drug delivery composition or device described herein has a storage modulus of at most about 600Pa, at most about 700Pa, at most about 800Pa, at most about 900Pa, at most about 1,000Pa, at most about 1,100Pa, at most about 1,200Pa, at most about 1,300Pa, at most about 1,400Pa, at most about 1,500Pa, at most about 1,600Pa, at most about 1,700Pa, at most about 1,800Pa, at most about 1,900Pa, at most about 2,000Pa, at most about 2,500Pa, at most about 3,000Pa, at most about 5,000Pa, at most about 10,000Pa, at most about 100,000Pa, at most about 1,000,000Pa, at most about 10,000,000Pa, or at most about 100,000,000 Pa.
The drug delivery compositions and devices described herein release one or more therapeutic agents under physiological conditions, such as in vivo. Release of the one or more therapeutic agents may occur at different rates depending on the composition of the composition or device (e.g., the nature and concentration of the hydrogel). For example, the release rate of the one or more therapeutic agents (the time at which the therapeutic agent is no longer part of the composition or device) may be on the order of minutes, hours, days, weeks, months or years. The therapeutic agent may be released by a variety of mechanisms, for example, by diffusion, chemical activity, enzymatic activity, or cellular mechanisms. In some embodiments, the drug delivery compositions and devices described herein are stable in vivo, such that they deliver the drug to the intended target within a suitable amount of time.
In certain embodiments, less than or equal to 90%, less than or equal to 80%, less than or equal to 70%, less than or equal to 60%, less than or equal to 50%, less than or equal to 40%, less than or equal to 30%, less than or equal to 20%, less than or equal to 10%, less than or equal to 5%, or less than or equal to 1% of the innate immune system activator is released in vivo within the following time period following administration (e.g., implantation) of the composition or device: 4 weeks, 3 weeks, 2 weeks, 10 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, 18 hours, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, 15 minutes, or 10 minutes.
In certain embodiments, greater than or equal to 99%, greater than or equal to 95%, greater than or equal to 90%, greater than or equal to 80%, greater than or equal to 70%, greater than or equal to 60%, greater than or equal to 50%, greater than or equal to 40%, greater than or equal to 30%, greater than or equal to 20%, greater than or equal to 10%, greater than or equal to 5%, or greater than or equal to 1% of the innate immune system activator is released in vivo within the following time period following administration (e.g., implantation) of the composition or device: 1 day, 18 hours, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, 15 minutes, or 10 minutes.
In certain embodiments, less than or equal to 90%, less than or equal to 80%, less than or equal to 70%, less than or equal to 60%, less than or equal to 50%, less than or equal to 40%, less than or equal to 30%, less than or equal to 20%, less than or equal to 10%, less than or equal to 5%, or less than or equal to 1% of any other innate immune system activator is released in vivo within the following time period following administration (e.g., implantation) of the composition or device: 4 weeks, 3 weeks, 2 weeks, 10 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, 18 hours, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, 15 minutes, or 10 minutes.
In certain embodiments, greater than or equal to 99%, greater than or equal to 95%, greater than or equal to 90%, greater than or equal to 80%, greater than or equal to 70%, greater than or equal to 60%, greater than or equal to 50%, greater than or equal to 40%, greater than or equal to 30%, greater than or equal to 20%, greater than or equal to 10%, greater than or equal to 5%, or greater than or equal to 1% of any other innate immune system activator is released in vivo within the following time period following administration (e.g., implantation) of the composition or device: 1 day, 18 hours, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, 15 minutes, or 10 minutes.
In certain embodiments, less than or equal to 90%, less than or equal to 80%, less than or equal to 70%, less than or equal to 60%, less than or equal to 50%, less than or equal to 40%, less than or equal to 30%, less than or equal to 20%, less than or equal to 10%, less than or equal to 5%, or less than or equal to 1% of the adaptive immune system activator is released in vivo within the following time period following administration (e.g., implantation) of the composition or device: 4 weeks, 3 weeks, 2 weeks, 10 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, 18 hours, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, 15 minutes, or 10 minutes.
In certain embodiments, greater than or equal to 99%, greater than or equal to 95%, greater than or equal to 90%, greater than or equal to 80%, greater than or equal to 70%, greater than or equal to 60%, greater than or equal to 50%, greater than or equal to 40%, greater than or equal to 30%, greater than or equal to 20%, greater than or equal to 10%, greater than or equal to 5%, or greater than or equal to 1% of the adaptive immune system activator is released in vivo within the following time period following administration (e.g., implantation) of the composition or device: 1 day, 18 hours, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, 15 minutes, or 10 minutes.
In certain embodiments, less than or equal to 90%, less than or equal to 80%, less than or equal to 70%, less than or equal to 60%, less than or equal to 50%, less than or equal to 40%, less than or equal to 30%, less than or equal to 20%, less than or equal to 10%, less than or equal to 5%, or less than or equal to 1% of any other adaptive immune system activator is released in vivo within the following time period following administration (e.g., implantation) of the composition or device: 4 weeks, 3 weeks, 2 weeks, 10 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, 18 hours, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, 15 minutes, or 10 minutes.
In certain embodiments, greater than or equal to 99%, greater than or equal to 95%, greater than or equal to 90%, greater than or equal to 80%, greater than or equal to 70%, greater than or equal to 60%, greater than or equal to 50%, greater than or equal to 40%, greater than or equal to 30%, greater than or equal to 20%, greater than or equal to 10%, greater than or equal to 5%, or greater than or equal to 1% of any other adaptive immune system activator is released in vivo within the following time period following administration (e.g., implantation) of the composition or device: 1 day, 18 hours, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, 15 minutes, or 10 minutes.
In certain embodiments, less than or equal to 90%, less than or equal to 80%, less than or equal to 70%, less than or equal to 60%, less than or equal to 50%, less than or equal to 40%, less than or equal to 30%, less than or equal to 20%, less than or equal to 10%, less than or equal to 5%, or less than or equal to 1% of the cytokine is released in vivo within the following time period following administration (e.g., implantation) of the composition or device: 4 weeks, 3 weeks, 2 weeks, 10 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, 18 hours, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, 15 minutes, or 10 minutes.
In certain embodiments, greater than or equal to 99%, greater than or equal to 95%, greater than or equal to 90%, greater than or equal to 80%, greater than or equal to 70%, greater than or equal to 60%, greater than or equal to 50%, greater than or equal to 40%, greater than or equal to 30%, greater than or equal to 20%, greater than or equal to 10%, greater than or equal to 5%, or greater than or equal to 1% of the cytokine is released in vivo within the following time period after administration (e.g., implantation) of the composition or device: 1 day, 18 hours, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, 15 minutes, or 10 minutes.
Preparation and administration of drug delivery compositions and devices
The present disclosure provides drug delivery compositions and devices comprising therapeutic agents as described herein. In certain embodiments, therapeutic agents are provided in drug delivery compositions and devices in effective amounts to treat and/or prevent a disease (e.g., a proliferative disease, such as cancer). In certain embodiments, an effective amount is a therapeutically effective amount for a particular therapeutic agent. In certain embodiments, an effective amount is a prophylactically effective amount for a particular therapeutic agent.
The drug delivery compositions and devices described herein can be prepared by any method known in the pharmaceutical art. In certain embodiments, such a method of preparation comprises the steps of: adding thiol-modified hyaluronic acid to the mold; adding a proinflammatory pathway inhibitor (e.g., a p38 MAPK pathway-mediated proinflammatory immune response inhibitor); optionally adding an adaptive immune response activator to the mold; optionally adding a chemokine or cytokine to the mold; optionally adding an innate immune response activator to the mold; adding a crosslinker to the mold (e.g., a thiol-reactive PEGDA crosslinker); and allowing the mixture to stand for at least 10 minutes, at least 15 minutes, at least 20 minutes, at least 25 minutes, at least 30 minutes, at least 35 minutes, at least 40 minutes, at least 45 minutes, at least 50 minutes, at least 55 minutes, at least 1 hour, at least 90 minutes, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, or at least 6 hours to cure.
In certain embodiments, the thiol-modified hyaluronic acid used to prepare the hydrogel (e.g.,) On a weight/volume basis, from about 1% to about 10%, from about 1% to about 5%, from about 1% to about 3%, or from about 1.5% to about 2.5%; the thiol-reactive PEGDA crosslinker used to make the hydrogel (e.g.,
To prepare standard tissue engineering application products known in the art, thiol-modified hyaluronic acid (e.g.,) Is about 1% w/v, a thiol-reactive PEGDA crosslinker (e.g.,) Is about 1% w/v. Thus, using 2% w/v thiol-modified hyaluronic acid (e.g.,) And 12.5% w/v thiol-reactive PEGDA crosslinker (e.g.,) Unexpectedly useful and advantageous biomaterials are provided in the disclosed drug delivery compositions and devices.
One skilled in the art will appreciate that other cross-linking agents may be used at suitable concentrations to form a hydrogel (e.g., a hyaluronic acid hydrogel). For example, in some embodiments, a hydrogel (e.g., a hyaluronic acid hydrogel) may be crosslinked by attaching: a thiol (for example, ) Methacrylate, hexadecane amide (e.g.,) And/or tyramine (e.g., COR)) To crosslink. In some embodiments, water condensationGums (e.g., hyaluronic acid hydrogels) can be directly crosslinked with: formaldehyde (for example,
In certain embodiments, the concentration of alginate used to make the hydrogel is from about 0.5% to about 2.5%, from about 0.75% to about 2.0%, or from about 1.0% to about 1.5% alginate on a weight/volume basis. In certain embodiments, the amount of 1M calcium chloride crosslinker solution used to prepare the hydrogel is about 5 μ L to 25 μ L, about 10 μ L to 20 μ L, or about 15 μ L. In some embodiments, the payload of interest may be loaded in: about 10 to 70 μ L of solvent (PBS or DMSO), 20 to 60 μ L of solvent (PBS or DMSO), about 30 to 50 μ L of solvent (PBS or DMSO), or about 40 μ L of solvent (PBS or DMSO).
The drug delivery compositions and devices may further comprise at least one excipient. In certain embodiments, the excipient is phosphate buffered saline, tris (hydroxymethyl) aminomethane, sodium chloride, potassium chloride, calcium chloride, magnesium sulfate, sodium bicarbonate, sodium phosphate, potassium phosphate, calcium nitrate, glucose, lactose, trehalose, sucrose, or a combination thereof. In certain embodiments, the excipient is phosphate buffered saline, tris (hydroxymethyl) aminomethane, sodium chloride, or a combination thereof. In certain embodiments, the excipient is phosphate buffered saline.
In certain embodiments, the drug delivery compositions and devices are free of nanoparticles or microparticles. Nanoparticles include particles between 1-100nm in size. The microparticles comprise particles having a size between 0.1 and 100 μm. In certain embodiments, the drug delivery compositions and devices are free of silica microparticles, polyethylene microparticles, polystyrene microparticles, polyester microparticles, polyanhydride microparticles, polycaprolactone microparticles, polycarbonate microparticles, or polyhydroxybutyrate microparticles. In certain embodiments, the drug delivery compositions and devices are free of porous silica microparticles.
In certain embodiments, the drug delivery compositions and devices include one or more organic solvents. In certain embodiments, the drug delivery compositions and devices comprise dimethyl sulfoxide (DMSO).
In certain embodiments, the drug delivery compositions and devices are free of organic solvents. In certain embodiments, either the organic solvent is not used in the preparation of the composition or device. In certain embodiments, the drug delivery compositions and devices are free of organic solvents. In certain embodiments, the drug delivery compositions and devices are substantially free of organic solvents. In certain embodiments, the drug delivery compositions and devices comprise less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% organic solvent on a weight basis. In certain embodiments, the drug delivery compositions and devices comprise less than 1000ppm, less than 500ppm, less than 400ppm, less than 300ppm, less than 200ppm, less than 100ppm, less than 50ppm, less than 40ppm, less than 30ppm, less than 20ppm, less than 10ppm, less than 1ppm, less than 10ppb, or less than 1ppb of organic solvent on a weight basis. In certain embodiments, the drug delivery composition is free of dimethyl sulfoxide (DMSO).
In certain embodiments, the drug delivery composition comprises an organic solvent. In certain embodiments, the organic solvent is cyclodextrin, methanol, ethanol, isopropanol, ethylene glycol, propylene glycol, or a combination thereof.
The drug delivery compositions and devices may be prepared, packaged and/or sold in bulk as a single unit dose and/or as a plurality of single unit doses. A "unit dose" is a discrete amount of a composition or device that contains a predetermined amount of a therapeutic agent. The amount of therapeutic agent is typically equal to the dose of therapeutic agent to be administered to the subject and/or a convenient fraction of that dose, e.g., one-half, one-third, or one-fourth of that dose.
The relative amounts of the therapeutic agent, excipient, and/or any other ingredient in the compositions or devices of the present disclosure will vary depending on the identity, size, and/or disorder of the subject being treated. For example, the composition or device may comprise the following amounts of therapeutic agent: 0.1% to 99% (w/w), 0.1% to 90% (w/w), 0.1% to 80% (w/w), 0.1% to 70% (w/w), 1% to 50% (w/w), 10% to 80% (w/w), 10% to 90% (w/w), 10% to 80% (w/w), 20% to 80% (w/w), 30% to 70% (w/w), or 40% to 60% (w/w).
Other pharmaceutically acceptable excipients may be used in the preparation of the provided drug delivery compositions and devices. These include inert diluents, dispersing and/or granulating agents, surfactants and/or emulsifiers, disintegrating agents, binders, preservatives, buffers, lubricants, and/or oils. Excipients such as cocoa butter and suppository waxes, colorants and coatings may also be present in the composition or device.
Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, dibasic calcium phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and mixtures thereof.
Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponges, cation exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked polyvinylpyrrolidone (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (cross-linked carboxymethyl cellulose), methyl cellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (VEEGUM), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.
Exemplary surfactants and/or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondroitin (chondlux), cholesterol, xanthan gum, pectin, gelatin, egg yolk, casein, lanolin, cholesterol, waxes, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glycerol monostearate and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxypolymethylene, polyacrylic acid, acrylic acid polymers and carboxyvinyl polymers), carrageenan, cellulose derivatives (e.g., sodium carboxymethylcellulose, powdered cellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate) Polyoxyethylene sorbitan
Exemplary binders include starches (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, and the like), natural and synthetic gums (e.g., acacia, sodium alginate, extracts of Irish moss, pantal, ghatti gum, mucilage of Issatchella shells, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose, cellulose acetate, poly (vinyl-pyrrolidone), magnesium aluminum silicate (VEEGUM) and larch arabinogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohols, and/or mixtures thereof.
Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcoholic preservatives, acidic preservatives and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.
Exemplary antioxidants include alpha-tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.
Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium ethylenediaminetetraacetate, calcium ethylenediaminetetraacetate, potassium ethylenediaminetetraacetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethanol, glycerol, hexahydropyridine, imidazolidinyl urea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.
Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, biphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
Exemplary acidic preservatives include vitamin a, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
Other preservatives include tocopherol, tocopherol acetate, deferoxamine mesylate, cetrimide, Butylated Hydroxyanisole (BHA), Butylated Hydroxytoluene (BHT), ethylenediamine, Sodium Lauryl Sulfate (SLS), Sodium Lauryl Ether Sulfate (SLES), sodium bisulfite, sodium pyrophosphite, potassium sulfite, potassium pyrophosphite, GLYDANT PLUS, PHENONIP, methyl paraben, germal 115, germamen II, NEOLONE, KATHON, and EUXYL.
Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium glucoheptonate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propionic acid, calcium levulinate, valeric acid, calcium hydrogen phosphate, phosphoric acid, tricalcium phosphate, calcium hydrogen phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, ringer's solution, ethanol, and mixtures thereof.
Exemplary lubricants include magnesium stearate, calcium stearate, stearic acid, silicon dioxide, talc, malt, glyceryl behenate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.
Exemplary natural oils include almond oil, avocado oil, babassu oil, bergamot oil, blackcurrant seed oil, borage oil, juniper oil, chamomile oil, canola oil, caraway oil, babassu oil, castor oil, cinnamon oil, cocoa butter, coconut oil, cod liver oil, coffee oil, corn oil, cottonseed oil, emu oil, eucalyptus oil, evening primrose oil, fish oil, linseed oil, geraniol oil, cucurbit oil, grapeseed oil, hazelnut oil, hyssop oil, isopropyl myristate oil, jojoba oil, kukui nut oil, lavandin oil, lavender oil, lemon oil, litsea cubeba oil, kukui nut oil, mallow nut oil, mango seed oil, meadowfoam seed oil, mink oil, nutmeg oil, olive oil, orange oil, atlantic palm oil, palm kernel oil, peach kernel oil, peanut oil, poppy seed oil, pumpkin seed oil, rapeseed oil, rice bran oil, rosemary oil, safflower oil, sandalwood oil, camellia oil, peppermint oil, sea buckthorn oil, sesame oil, shea butter, silicone oil, soybean oil, sunflower seed oil, tea tree oil, thistle oil, toon oil, vetiver oil, walnut oil, and wheat germ oil. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.
Although the description of the drug delivery compositions provided herein is primarily directed to compositions suitable for administration to humans, those skilled in the art will appreciate that such compositions are generally suitable for administration to a variety of animals. It will be readily appreciated that modifications to a drug delivery composition suitable for administration to humans to render the composition suitable for administration to a variety of animals may be made, and that such modifications may be designed and/or made by one of ordinary skill in the veterinary chemist's art through routine experimentation.
The drug delivery compositions and devices provided herein are typically formulated in a size (e.g., volume) and weight suitable for the intended use (e.g., surgical implantation) for ease of administration. However, it will be understood that the total amount of a composition or device of the present disclosure (e.g., the number of implanted devices) will be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors, including the disease being treated and the severity of the disease; the activity of the particular active ingredient used; the specific composition used; the age, weight, general health disorder, sex, and diet of the subject; time of administration, route of administration and rate of excretion of the particular active ingredient used; the duration of the treatment; drugs used in combination or concomitantly with the specific active ingredient employed; and factors well known in the medical arts.
The drug delivery compositions and devices provided herein can be administered by surgical implantation. For example, the drug delivery composition or device may be administered in the void volume of a resected tumor by surgical implantation. As a further example, the drug delivery composition or device may be administered by surgical implantation and secured with a biological adhesive. In certain embodiments, the drug delivery composition or device is immobilized with a bioadhesive in the void volume of the resected tumor.
In certain embodiments, the drug delivery composition or device is administered by surgical implantation at a site within the void volume of an excised tumor as follows: 100cm, 90cm, 80cm, 70cm, 60 cm. 50cm, 40cm, 30cm, 20cm, 10cm, 9cm, 8cm, 7cm, 6cm, 5cm, 4cm, 3cm, 2cm, 1cm, 9mm, 8mm, 7mm, 6mm, 5mm, 4mm, 3mm, 2mm or 1 mm. In certain embodiments, the void volume of the resected tumor is the void volume of the resected tumor-bearing organ (e.g., lung, kidney, pancreas, liver, colon, testis, ovary, breast, appendix, bladder). In certain embodiments, the void volume of the resected tumor is the void volume of the resected portion of the tumor-bearing organ (e.g., lung, kidney, pancreas, liver, colon, testis, ovary, breast, appendix, bladder).
In certain embodiments, the precursor component of the hydrogel (e.g., hyaluronic acid) and the crosslinking agent are separately administered to the subject (e.g., at the site of tumor resection), thereby forming a drug delivery composition in vivo. In certain embodiments, the precursor component of the hydrogel (e.g., hyaluronic acid) and the crosslinking agent are administered sequentially. In certain embodiments, the precursor component of the hydrogel (e.g., hyaluronic acid) and the crosslinking agent are administered simultaneously. In certain embodiments, the precursor component of the hydrogel (e.g., hyaluronic acid) and the crosslinking agent are administered as a mixture. In certain embodiments, administration is by injection.
In certain embodiments, the alginate and the cross-linking agent are separately administered to the subject (e.g., at the site of tumor resection), thereby forming a drug delivery composition in vivo. In certain embodiments, the alginate and the cross-linking agent are administered sequentially. In certain embodiments, the alginate and the cross-linking agent are administered simultaneously. In certain embodiments, the alginate and the cross-linking agent are administered as a mixture. In certain embodiments, administration is by injection.
The exact amount of therapeutic agent required to achieve an effective amount will vary from individual to individual, depending upon, for example, the species, age, and general disorder of the individual, the severity of the side effect or condition, the identity of the particular agent, and the like.
In certain embodiments, an effective amount of a composition or device administered to a 70kg adult may comprise from about 0.0001mg to about 3000mg, from about 0.0001mg to about 2000mg, from about 0.0001mg to about 1000mg, from about 0.001mg to about 1000mg, from about 0.01mg to about 1000mg, from about 0.1mg to about 1000mg, from about 1mg to about 100mg, from about 10mg to about 1000mg, or from about 100mg to about 1000 mg.
In certain embodiments, the dosage level of the composition or device should be sufficient to deliver from about 0.001mg/kg to about 100mg/kg, from about 0.01mg/kg to about 50mg/kg, from about 0.1mg/kg to about 40mg/kg, from about 0.5mg/kg to about 30mg/kg, from about 0.01mg/kg to about 10mg/kg, from about 0.1mg/kg to about 10mg/kg, or from about 1mg/kg to about 25mg/kg of the subject's body weight of any therapeutic agent present in the composition per day to achieve the desired therapeutic effect.
It is understood that the dosage ranges described herein provide guidance for administering the provided drug delivery compositions and devices to adults. The amount administered to, for example, a child or adolescent can be determined by a physician or skilled artisan and can be the same or lower than the amount administered to an adult.
It is also understood that the compositions and devices as described herein may be administered in combination with one or more other pharmaceutical agents. For example, the compositions and devices may be administered in combination with other pharmaceutical agents that reduce and/or alter their metabolism, inhibit their secretion, and/or alter their distribution in the body. It is also understood that other therapies used may achieve a desired effect for the same condition, and/or they may achieve different effects.
The compositions and devices may be administered simultaneously with or before or after one or more other drugs, which may be used, for example, as a combination therapy. The pharmaceutical agent includes a therapeutically active agent. The pharmaceutical agent also includes a prophylactically active agent. Each of the other pharmaceutical agents may be administered at a dose and/or on a schedule determined for that agent. Other pharmaceutical agents will be administered separately at different doses and/or different routes of administration. The particular combination employed in the regimen will take into account the compatibility of the drug delivery composition with other pharmaceutical agents and/or the desired therapeutic and/or prophylactic effect to be achieved. In general, it is desirable that the other pharmaceutical agents used in combination are used at a level not exceeding their individual use levels. In some embodiments, the level of combined use will be lower than the level used alone.
Exemplary other pharmaceutical agents include, but are not limited to, antiproliferative agents, anticancer agents, anti-inflammatory agents, immunosuppressive agents, and pain-relieving agents. Drugs include small molecule therapeutics such as pharmaceutical compounds (e.g., compounds provided in federal regulations (CFR) approved by the U.S. food and drug administration), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucins, lipoproteins, synthetic polypeptides or proteins, small molecules that are linked to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.
In certain embodiments, the drug delivery compositions and devices are cell-free. In certain embodiments, the drug delivery compositions and devices are free of adoptively transferred cells. In certain embodiments, the drug delivery compositions and devices are free of T cells. In certain embodiments, the additional pharmaceutical agent is not an adoptively transferred cell. In certain embodiments, the other pharmaceutical agent is not a T cell. In certain embodiments, the drug delivery compositions and devices are free of tumor antigens. In certain embodiments, the drug delivery compositions and devices are free of ex vivo loaded tumor antigens.
In certain embodiments, a "drug delivery composition" refers to a composition in liquid form (e.g., a viscous solution). In certain embodiments, the term "drug delivery device" refers to a composition in solid form (e.g., a hydrogel). In certain embodiments, the transition from the composition to the device can occur upon sufficient crosslinking such that the resulting material has a storage modulus consistent with a solid form, allowing it to be physically manipulated and implanted during surgery. Accordingly, drug delivery devices in solid form may be particularly suitable for performing the intended use of the present disclosure (e.g., surgical implantation).
In certain embodiments, the drug delivery composition and/or drug delivery device is prepared in vivo prior to implantation (e.g., in the operating room or immediately following surgery). In certain embodiments, the drug delivery composition and/or drug delivery device is prepared within 24 hours, 18 hours, 12 hours, 11 hours, 10 hours, 9 hours, 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 20 minutes, 10 minutes, 5 minutes, or 1 minute of implantation in vivo.
In certain embodiments, the drug delivery composition and/or drug delivery device is prepared prior to implantation in vivo. In certain embodiments, the drug delivery composition and/or drug delivery device is prepared within 31 days, 28 days, 21 days, 14 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day of implantation in vivo.
In certain embodiments, the drug delivery composition is prepared within 1 year, 10 months, 8 months, 6 months, 4 months, 3 months, 2 months, 31 days, 28 days, 21 days, 14 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day of its use in a therapeutic setting. In certain embodiments, the prepared drug delivery composition is subsequently used to prepare a corresponding drug delivery device by: the crosslinker as described herein is added within 31 days, 28 days, 21 days, 14 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, 18 hours, 12 hours, 11 hours, 10 hours, 9 hours, 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 20 minutes, 10 minutes, 5 minutes, or 1 minute of in vivo implantation.
The disclosure also includes kits. The provided kits can comprise the compositions and/or devices described herein and a container (e.g., a vial, ampoule, bottle, syringe and/or dispenser package, or other suitable container). In some embodiments, provided kits may optionally further comprise a second container comprising a pharmaceutical excipient for diluting or suspending a pharmaceutical composition or compound described herein. In some embodiments, the kit comprises precursor components (e.g., hyaluronic acid and a cross-linking agent; or alginate and a cross-linking agent) that result in a drug delivery composition and/or drug delivery device.
In certain embodiments, the kit comprises a hydrogel and a proinflammatory pathway inhibitor (e.g., a p38MAPK pathway-mediated proinflammatory immune response inhibitor). In certain embodiments, the kit comprises a hydrogel, a proinflammatory pathway inhibitor (e.g., a p38MAPK pathway-mediated proinflammatory immune response inhibitor), and an innate immune response activator. In certain embodiments, the kit comprises a hydrogel, a proinflammatory pathway inhibitor (e.g., a p38MAPK pathway-mediated proinflammatory immune response inhibitor), and a cytokine. In certain embodiments, the kit comprises a hydrogel, a proinflammatory pathway inhibitor (e.g., a p38MAPK pathway-mediated proinflammatory immune response inhibitor), and an adaptive immune response activator. In certain embodiments, the kit further comprises an innate immune function activator. In certain embodiments, the kit further comprises a cytokine. In certain embodiments, the kit further comprises an adaptive immune response activator. In certain embodiments, the kit further comprises a macrophage effector function modulator. In certain embodiments, the kit further comprises an additional adaptive immune response activator. In certain embodiments, the kit further comprises an oncogenic virus, a radioisotope, an immunomodulatory chemotherapeutic agent, a targeting agent, or a combination thereof. In certain embodiments, the kit comprises any of the drug delivery compositions described herein. In certain embodiments, the kit comprises any of the drug delivery devices described herein.
In certain embodiments, the kit does not contain a chemotherapeutic agent. In certain embodiments, the kit is free of cytotoxic agents.
In certain embodiments, the kits described herein further comprise instructions for using the kit. The kits described herein may also include information required by regulatory agencies such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information contained in the kit is prescription drug information. In certain embodiments, the kit and instructions for use provide for the treatment of cancer. The kits described herein may comprise one or more other pharmaceutical agents described herein as a separate component.
Methods of treatment and uses
The present disclosure provides methods for treating and/or preventing a proliferative disease, such as a cancer (e.g., sarcoma, carcinoma, lymphoma, germ cell tumor, or blastoma), in a subject using the drug delivery compositions and devices described herein. In some embodiments, the compositions and/or devices described herein are used to treat resectable tumors. In some embodiments, the compositions and/or devices described herein are used to treat lymphoma present in tissues other than the spleen or lymphatic system (e.g., thyroid or stomach).
In some embodiments, the drug delivery compositions and devices described herein can be used to treat cancer. In some embodiments, the drug delivery compositions and devices described herein can be used to delay the onset of cancer, slow the progression of cancer, or alleviate a symptom of cancer. In some embodiments, the drug delivery compositions and devices described herein can be used to prevent cancer. In some embodiments, the drug delivery compositions and devices described herein can be used to prevent primary tumor regrowth. In some embodiments, the drug delivery compositions and devices described herein can be used to prevent tumor metastasis. In some embodiments, the drug delivery compositions and devices described herein are administered in combination with other compounds, drugs, or therapeutic agents to treat cancer.
In certain embodiments, the cancer is a solid tumor. In certain embodiments, the cancer is a sarcoma, carcinoma, lymphoma, germ cell tumor, blastoma, or a combination thereof. In certain embodiments, the tumor is a sarcoma, carcinoma, lymphoma, germ cell tumor, blastoma, or a combination thereof.
In some embodiments, the drug delivery compositions and devices described herein can be used to treat cancers including, but not limited to, acoustic neuroma; adenocarcinoma; adrenal cancer; anal cancer; angiosarcomas (e.g., lymphangiosarcoma, lymphangial endotheliosarcoma, angiosarcoma); appendiceal carcinoma; benign monoclonal gamma globulinosis; biliary cancer (e.g., cholangiocarcinoma); biliary tract cancer; bladder cancer; bone cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, breast cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma), glioblastoma, glioma (e.g., astrocytoma, oligodendroglioma, medulloblastoma); bronchial cancer; carcinoid tumors; a cardiac tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial cancer; ductal carcinoma in situ; ependymoma; endothelial sarcoma (e.g., kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the esophagus, barrett's adenocarcinoma); ewing's sarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma); familial hypereosinophilia; gallbladder cancer; stomach cancer (e.g., gastric adenocarcinoma); gastrointestinal stromal tumors (GIST); germ cell cancer; head and neck cancer (e.g., squamous cell carcinoma of the head and neck), oral cancer (e.g., squamous cell carcinoma of the oral cavity), laryngeal cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer); hematopoietic cancers (e.g., lymphoma, primary pulmonary lymphoma, broncho-associated lymphoid tissue lymphoma, splenic lymphoma, lymph node marginal zone lymphoma, pediatric B-cell non-hodgkin's lymphoma); hemangioblastoma; histiocytosis; hypopharyngeal carcinoma; inflammatory myofibroblastic tumors; immune cell amyloidosis; kidney cancer (e.g., nephroblastoma, also known as wilms' tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular carcinoma (HCC), malignant liver cancer); lung cancer (e.g., bronchial cancer, Small Cell Lung Cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma); leiomyosarcoma (LMS); melanoma; midline ductal carcinoma; multiple endocrine tumor syndrome; muscle cancer; mesothelioma; nasopharyngeal carcinoma; neuroblastoma; neurofibromas (e.g., neurofibromas type 1 or type 2 (NF); Schwann cell neoplasia); neuroendocrine cancers (e.g., gastroenteropancreatic neuroendocrine tumors (GEP-NET), carcinoid tumors); osteosarcoma (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonic carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic cancer, papillary mucinous neoplasms in the ducts (IPMN), islet cell tumor of pancreas); parathyroid cancer; papillary adenocarcinoma; penile cancer (e.g., paget's disease of the penis and scrotum); pharyngeal cancer; pineal tumor; pituitary cancer; pleuropulmonary blastoma; primitive Neuroectodermal Tumors (PNT); plasmacytoma formation; a paraneoplastic syndrome; an intraepithelial neoplasm; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; retinoblastoma; salivary gland cancer; skin cancer (e.g., Squamous Cell Carcinoma (SCC), Keratoacanthoma (KA), melanoma, Basal Cell Carcinoma (BCC)); small bowel cancer (e.g., appendiceal cancer); soft tissue sarcomas (e.g., Malignant Fibrous Histiocytoma (MFH), liposarcoma, Malignant Peripheral Nerve Sheath Tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland cancer; gastric cancer; small bowel cancer; sweat gland cancer; a synovial tumor; testicular cancer (e.g., sperm cell cancer, testicular embryo cancer); thymus gland cancer; thyroid cancer (e.g., papillary carcinoma of the thyroid, Papillary Thyroid Carcinoma (PTC), medullary thyroid carcinoma); cancer of the urethra; and vulvar cancer (e.g., Paget's disease of the vulva), or any combination thereof.
In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is a skin cancer. In certain embodiments, the cancer is melanoma. In certain embodiments, the cancer is lung cancer. In certain embodiments, the cancer is renal cancer. In certain embodiments, the cancer is liver cancer. In certain embodiments, the cancer is pancreatic cancer. In certain embodiments, the cancer is colorectal cancer. In certain embodiments, the cancer is bladder cancer. In certain embodiments, the cancer is lymphoma. In certain embodiments, the cancer is prostate cancer. In certain embodiments, the cancer is thyroid cancer.
In some embodiments, the drug delivery compositions and devices described herein can be used to treat adenocarcinoma, adrenal cancer, anal cancer, angiosarcoma, appendiceal cancer, biliary cancer, bladder cancer, bone cancer, brain cancer, breast cancer, bronchial cancer, carcinoid tumors, cardiac tumors, cervical cancer, choriocarcinoma, chordoma, colorectal cancer, connective tissue cancer, craniopharyngeal tumor, ductal carcinoma in situ, endothelial sarcoma, endometrial cancer, ependymoma, epithelial cancer, esophageal cancer, ewing's sarcoma, eye cancer, familial hypereosinophilia, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell cancer, head and neck cancer, hemangioblastoma, histiocytosis, hodgkin lymphoma, hypopharynx cancer, inflamed myofibroblastoma, intraepithelial tumors, immune cell amyloidosis, kaposi's sarcoma, kidney cancer, lung cancer, leiomyosarcoma (LMS), melanoma, midline catheter carcinoma, multiple endocrine tumor syndrome, sarcoid, mesothelioma, myeloproliferative disease (MPD), nasopharyngeal carcinoma, neuroblastoma, neurofibroma, neuroendocrine carcinoma, non-hodgkin's lymphoma, osteosarcoma, ovarian carcinoma, pancreatic carcinoma, paraneoplastic syndrome, parathyroid carcinoma, papillary adenocarcinoma, penile carcinoma, pharyngeal carcinoma, pheochromocytoma, pinealoma, pituitary carcinoma, pleuropulmonoblastoma, Primitive Neuroectodermal Tumor (PNT), plasmacytoma, prostate carcinoma, rectal carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland carcinoma, sebaceous gland carcinoma, small intestine carcinoma, soft tissue sarcoma, gastric carcinoma, sweat gland carcinoma, synovial carcinoma, testicular carcinoma, thymus carcinoma, thyroid carcinoma, urinary tract carcinoma, uterine carcinoma, vaginal carcinoma, vascular carcinoma, vulval carcinoma, or combinations thereof.
In some embodiments, the drug delivery compositions and devices described herein can be used to treat and/or prevent solid tumors and metastases.
For example, in some embodiments, the methods comprise administering a drug delivery composition or device described herein (e.g., comprising a hydrogel biomaterial and an inhibitor of the p38 MAPK pathway) to a target site of a subject who has recently undergone tumor resection. In some embodiments, the target site is a tumor resection site. In some embodiments, the target site is a sentinel lymph node. In some embodiments, the target site is a draining lymph node. In some embodiments, the target site is a site where cancer cells have been treated or killed by a previous cancer treatment, such as chemotherapy or radiation.
In some embodiments, the drug delivery composition (e.g., comprising a hydrogel biomaterial and a p38 MAPK pathway inhibitor) administered to the target site is a preformed gel that can be administered to the target site by implantation. In some embodiments, the drug delivery composition (e.g., comprising the precursor component of the hydrogel and the p38 MAPK pathway inhibitor) administered to the target site is in an injectable form (e.g., a liquid). In some embodiments, administration as described herein involves administration of one Or precursor components of a plurality of biomaterials (e.g., hydrogels) that interact or react in situ to form a gel as described herein; in some such embodiments, such interactions or reactions involve crosslinking, which in some embodiments occurs naturally, and in some embodiments may occur through the application of reagents (e.g., catalysts and/or reactants) and/or conditions (e.g., one or more of heat, pH, pressure, specific wavelengths of electromagnetic radiation). In some embodiments, a biomaterial (e.g., a hydrogel) can be attached to a surface by attaching a thiol (e.g.,
In certain embodiments, the methods described herein comprise implanting (e.g., via a biomaterial gel or precursor set thereof as described herein) an effective amount of a drug delivery composition or device described herein in a subject. In certain embodiments, the methods described herein comprise surgically implanting in a subject an effective amount of a drug delivery composition or device described herein. In certain embodiments, the methods described herein further comprise implanting the drug delivery composition or device after surgical resection of the tumor. In certain embodiments, the methods described herein further comprise implanting a drug delivery composition or device at the tumor resection site. In certain embodiments, the methods described herein further comprise implanting a drug delivery composition or device in the void volume of the resected tumor. In certain embodiments, the methods described herein further comprise implanting a drug delivery composition or device at the tumor resection site during the tumor resection procedure.
In certain embodiments, the methods described herein comprise administering (e.g., implanting) the drug delivery composition or device after removing greater than or equal to 50 wt.%, greater than or equal to 55 wt.%, greater than or equal to 60 wt.%, greater than or equal to 65 wt.%, greater than or equal to 70 wt.%, greater than or equal to 75 wt.%, greater than or equal to 80 wt.%, greater than or equal to 85 wt.%, greater than or equal to 90 wt.%, greater than or equal to 95 wt.%, greater than or equal to 96 wt.%, greater than or equal to 97 wt.%, greater than or equal to 98 wt.%, or greater than or equal to 99 wt.% of the resected tumor. In certain embodiments, the methods described herein comprise administering (e.g., implanting) a drug delivery composition or device after removing greater than or equal to 50 vol%, greater than or equal to 55 vol%, greater than or equal to 60 vol%, greater than or equal to 65 vol%, greater than or equal to 70 vol%, greater than or equal to 75 vol%, greater than or equal to 80 vol%, greater than or equal to 85 vol%, greater than or equal to 90 vol%, greater than or equal to 95 vol%, greater than or equal to 96 vol%, greater than or equal to 97 vol%, greater than or equal to 98 vol%, or greater than or equal to 99 vol% of the resected tumor.
In certain embodiments, the methods described herein do not include administering (e.g., implanting) a drug delivery composition or device to the site adjacent to the tumor. In certain embodiments, the methods described herein do not include administering (e.g., implanting) a drug delivery composition or device to a tumor without resecting the tumor.
In certain embodiments, the drug delivery compositions and devices described herein are administered in combination with one or more other therapeutic agents described herein. In certain embodiments, the additional therapeutic agent is an anti-cancer agent.
In certain embodiments, the subject treated is a mammal. In certain embodiments, the subject is a human. In certain embodiments, the subject is a human patient who has received neoadjuvant (pre-operative) chemotherapy. In certain embodiments, the subject is a human patient who has received neoadjuvant radiotherapy. In certain embodiments, the subject is a human patient who has received neoadjuvant chemotherapy and radiation therapy. In certain embodiments, the subject is a human patient who has received neoadjuvant molecule targeted therapy. In certain embodiments, the subject is a human patient who has received neoadjuvant immunotherapy, including immune checkpoint blockade (e.g., anti-CTLA-4, anti-PD-1, and/or anti-PD-L1). In certain embodiments, the subject is a human patient not receiving neoadjuvant immunotherapy, including immune checkpoint blockade (e.g., anti-CTLA-4, anti-PD-1, and/or anti-PD-L1). In certain embodiments, the subject is a human patient whose tumor is objectively unresponsive to neoadjuvant therapy (as defined by the criteria for assessment of solid tumor Response (RECIST) or the criteria for immune-related response (irRC)) (e.g., stable disease, progressive disease). In certain embodiments, the subject is a human patient whose target lesion is objectively responsive (e.g., partially responsive, fully responsive) to neoadjuvant therapy. Non-target lesions may show incomplete responses, stable disease, or progressive disease. In certain embodiments, the subject is a human patient eligible to receive immunotherapy as standard of care in an assisted (post-operative) environment. In certain embodiments, the subject is a domestic animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal, such as a rodent, pig, dog, or non-human primate. In certain embodiments, the subject is a non-human transgenic animal, such as a transgenic mouse or a transgenic pig.
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