Compositions and methods for the treatment of cancer

Abstract

This invention provides a localized delivery method for immunotherapeutic agents to suppress specific adverse events that may occur during systemic administration of immunotherapeutic agents in cancer treatment. [Solution] A drug delivery composition and device useful for the treatment and / or prevention of cancer and metastatic tumors is provided. For example, a drug delivery composition and / or device is provided comprising a biodegradable scaffold or biomaterial containing 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 composition and / or device may further contain one or more agents that activate the innate immune system (e.g., STING agonists) and / or the adaptive immune system (e.g., anti-PD-1 antibodies). In some embodiments, the drug delivery composition and / or device can be administered to the tumor resection site.

Description

[Technical Field]

[0001] Cross-references to related applications This application relates to U.S. Provisional Patent Application No. 62 / 645,613, filed on March 20, 2018, and January 11, 2019. Priority under 35 U.S. SC § 119(e) to National Provisional Patent Application No. 62 / 791,481 filed on [date] This assertion is made, and each of these is incorporated herein by reference in whole. [Background technology]

[0002] background Systemic administration of medicines, nutrients, or other substances into the circulatory system affects the entire body. As a systemic route of administration, enteral (for example, oral administration that leads to drug absorption through the gastrointestinal tract) is an option. This includes administration by hand (intravenous, intramuscular, and subcutaneous injection) and parenteral administration (e.g., intravenous, intramuscular, and subcutaneous injection). The administration of therapeutic agents typically relies on these systemic routes of administration, which can lead to undesirable side effects. It may produce an effect. In some cases, certain promising therapeutic agents may be more effective than current administration. Due to the associated toxicity and limiting factors of the law and system, development is extremely difficult. .

[0003] Surgical intervention is often the first-line treatment for solid tumors, and is generally considered a form of cancer treatment. It is used in combination with systemic administration of the drug. However, immunosuppression induced by surgery is This ultimately leads to the death of many patients due to various metabolic and endocrine response changes. This has been linked to the development of postoperative sepsis complications and tumor metastasis (Smyth, MJ et al. ., Nature Reviews Clinical Oncology, 2016, 13, 143-158). [Overview of the project]

[0004] Abstract Systemic administration of immunotherapy agents can have adverse side effects, such as the elimination of non-cancerous cells, including non-tumor-specific immune cells. Induction of undesirable toxicity to cells and / or tissues, as well as / or therapeutic effects There is a demand for high doses to achieve sufficient concentration at the target site to produce a response. Surgical removal of tumors can lead to immunosuppression. Surgical procedures can also affect cells. Stress can be induced, which can promote one or more physiological processes, such as wound healing after an injury. This may be accompanied by activation of a response. Such responses may be, for example, neurological, inflammatory, and / or Activation of angiogenic signaling pathways is one example, which also contributes to cancer growth and / or It may promote propagation through metastasis. Inflammation may occur at the surgical site after tumor resection. Sexual changes include, for example, the recruitment of immune and / or inflammatory cell types, and / or body The release of humoral factors can be cited. Local inflammatory wound responses and systemic inflammatory processes. Together, they activate dormant micrometastases or induce the proliferation of residual cancer cells. This could increase the risk of cancer recurrence.

[0005] This disclosure includes, in particular, certain conventional approaches to treating cancer. This disclosure provides insights, including the identification of the source of problems in prior art. For example, this disclosure relates to immunotherapy agents. Certain adverse events that may occur with systemic administration of this drug (e.g., skin rash, hepatitis, diarrhea, colon Inflammation of the pituitary gland, hypophysitis, thyroiditis, and adrenal insufficiency may be related to immunity, or at least partially. This can be attributed to the exposure of non-tumor-specific immune cells to systemically administered immunotherapy drugs. This disclosure recognizes that, in particular, it is sufficient in tumors to induce the desired response. To achieve the desired concentration, the high doses typically required for systemic administration are necessary. It is recognized that it may contribute to or cause undesirable effects. In particular, this problem is solved by providing localized delivery of immunotherapy agents. This system provides a mechanism that, in particular, concentrates the effects of the drug where it is needed. By shrinking it, its effectiveness can be improved.

[0006] Furthermore, this disclosure describes certain immunological methods classically used to treat autoimmune conditions. If the regulator is administered as described herein, it will not work if not administered in that manner. Contrary to expectations regarding anti-cancer immunomodulatory compounds, target toxicity is predicted to be present. Despite this, it provides insight into the possibility of its usefulness in cancer treatment. Therefore, this disclosure relates to the use of an agent that was not previously considered useful for cancer treatment. To explain the usefulness of, and furthermore, to be particularly effective for these agents and other agents and / or Instruct on the preferred delivery and administration strategy.

[0007] This disclosure, in particular, describes how one or more p38 mitogen-activated proteins are present at the tumor resection site. Inflammation mediated by the protein kinase (MAPK) pathway (e.g., by administration of a p38 MAPK inhibitor) By inhibiting the sex immune response, the risk of cancer recurrence is reduced, thereby improving survival. It is recognized that it can be extended. This disclosure relates to the delivery target site of one or more immunomodulators ( For example, the tumor is removed by chemotherapy or radiation, and / or Localizing delivery to the site where cancer cells have been treated or killed, thereby the immunomodulatory agent To provide a drug delivery system that can concentrate its effects on the target site where it is needed. A drug delivery system may be particularly useful for treating cancer. In particular, a drug delivery system may be, for example In some embodiments, after tumor resection, adverse side effects and / or systemic exposure may occur. To minimize the risk of, for example, tumor recurrence and / or metastasis (e.g., the onset of the disease) One or more inflammations in order to treat cancer (delaying or reducing the severity of the disease) Triggering pathways (e.g., pro-inflammatory immune responses mediated by the p38 MAPK pathway; e.g., Figures 4-6) Deliver one or more therapeutic agents that act on (e.g., inhibit) (see reference).

[0008] In some respects, what is provided is the target site of the cancerous subject (for example) In the tumor resection site, biomaterials and p38 mitogen-activated protein kinase Intraoperative administration of a composition containing an inhibitor of the pro-inflammatory immune response mediated by the (MAPK) pathway. This method includes the following:

[0009] In one aspect, biomaterials have a storage modulus of approximately 500 Pa to approximately 50,000 Pa. In one embodiment, the biomaterial is a hydrogel or contains a hydrogel. The biomaterial is hyaluronic acid or contains it. In one embodiment, the biomaterial is cross-linked hyaluronic acid or contains the same. In one embodiment, a biomaterial This is hyaluronic acid crosslinked with polyethylene glycol crosslinking agent, or contains this. nothing.

[0010] In one embodiment, the method does not involve adoptive transfer of T cells to a target. The method does not involve administering tumor antigens to a target. In one embodiment, the method is micro This does not include administering particles as the target.

[0011] In one embodiment, the inhibitor is located at the ATP and / or allosteric binding site of P38 MAPK. It is a p38α / βMAPK inhibitor that binds to the position. In one embodiment, the p38α / βMAPK inhibitor is a It is a losmapimod.

[0012] In one embodiment, the composition further comprises an activator of innate immunity. Innate immunity activators include interferon gene stimulators. n genes:STING) are agonists. In one aspect, the activators of innate immunity are Toll It is a TLR7 and / or TLR8 ("TLR7 / 8") agonist. In one embodiment, The composition modulates T cells, natural killer (NK) cells, monocytes, and / or dendritic cells. Further comprising adaptive immune activators and / or cytokines. In one embodiment, a combination The product further modulates cytokines that regulate T cells, NK cells, monocytes, and / or dendritic cells. Includes, but is not limited to, IL-15 superagonists. Examples include IFN-α, IFN-β, IFN-γ, and combinations thereof. In some embodiments... Furthermore, the composition includes, for example, a cyclooxygenase (COX) inhibitor, including a COX-2 inhibitor. include.

[0013] Those skilled in the art will know of certain COX inhibitors and / or other anti-inflammatory agents (e.g., nonsteroidal anti-inflammatory drugs). Inflammatory drugs (NSAIDs and / or anti-inflammatory analgesics) affect the p38 MAPK pathway or its components. You will understand that it can act as a modifying factor (e.g., an inhibitor) (for example, as follows: See the following for details: Esposito et al., "Non-steroidal anti-inflammatory drugs in P arkinson's disease" Experimental Neurology 205: 295-312 (2007); Desai et al., "Mecha Phytonutrient Modulation of Cyclooxygenase-2 (COX-2) and Inflammation R "elated to Cancer" Nutrition and Cancer, 70: 350-375 (2018); Huang et al., "MAPK / ERK s ignal pathway involved expression of COX-2 and VEGF by IL-1beta induced in human "Endometriosis stomal cells in vitro" Int J Clin Exp Pathol, 6: 2129-2136 (2013); and Di Mari et al., “HETEs enhance IL-1-mediated COX-2 expression via augmentation of message stability in human colonic myofibroblasts” Am J Physiol-Gastrointest Liver Physiol., 293: 2092-2101 (2007). Therefore, in some aspects, COX- 2. Inhibitors or other anti-inflammatory agents (e.g., nonsteroidal anti-inflammatory drugs (NSAIDs) and / or anti-inflammatory drugs) The inflammatory analgesic may be a p38 MAPK inhibitor as described herein. (and / or may be used as such); alternatively, or in addition, in some manner Such COX-2 inhibitors or other anti-inflammatory agents (e.g., anti-inflammatory analgesics) are used herein. It can be used in combination with other p38 MAPK inhibitors, as described.

[0014] In one embodiment, the biomaterial forms a matrix or depot, and the inhibitor is biological It is present in the material. In one embodiment, the inhibitor is released by diffusion through the biomaterial. In one embodiment, the biomaterial is biodegradable in vivo. The material was tested in vivo by transplanting the biomaterial into the mammary fat body of mice. In such cases, less than 10% of the biomaterial remains in vivo four months after transplantation, which is particularly important. It is marked. In one aspect, the biomaterial is a composition comprising the biomaterial and rosmapimod. When a substance is tested in vitro by placing it in PBS (pH 7.4), among the rosmapimods... Substances less than 100% are characterized by being released from biological materials within 3 hours. In this case, the biomaterial is a composition containing the biomaterial and rosmapimod, and is used in the mammary glands of mice. When tested in vivo by transplantation into the fat body, 5 of rosmapimod Less than 0% is characterized by being released 8 hours after transplantation in vivo. In this case, when the biomaterial is evaluated 24 hours after administration, the inhibitor is in the solution. Compared to when administered in the same manner, more inhibitors are observed at the tumor resection site. It is characterized by extending the release of the inhibitor so that it is present.

[0015] In one aspect, administration is by transplantation. In another aspect, administration is by injection. This is due to the administration of one or more precursor structures of a biomaterial. This makes it possible to inject the active ingredients and to form biomaterials at the tumor resection site. This includes doing so. In one embodiment, where the target site is the tumor resection site, the tumor resection site is the flesh. It is characterized by the absence of residual tumor antigens in the eye. In one embodiment, cancer is metastatic It is cancer. In one aspect, the method involves administering the composition to a subject and then at least This further includes monitoring another metastatic site.

[0016] Details of certain aspects of the present invention are described herein. Other features, objectives and The advantages will be evident from the detailed description, examples, and claims.

[0017] definition As used herein, the term “salt” means any and all salts, and drugs. It includes scientifically acceptable salts.

[0018] The term "pharmaceutically acceptable salt" refers to a salt that, within the bounds of sound medical judgment, does not exhibit excessive toxicity. Without causing irritation, allergic reactions, etc., for example, with human and / or animal tissues A salt suitable for contact use, with a reasonable benefit / risk ratio. It refers to a pharmaceutically acceptable salt, which is well known in the field. For example, Berge et al. The following is referenced in the specification: J. Pharmaceutical Sciences, 1977, 66, 1-19 The pharmaceutically acceptable salts are described in detail. Use in accordance with certain aspects of this disclosure. Suitable pharmaceutically acceptable salts can be derived from inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts include hydrochloric acid and hydrogen bromide. By inorganic acids such as acids, phosphoric acid, sulfuric acid, and perchloric acid, or by acetic acid, oxalic acid, maleic acid By acid, tartaric acid, citric acid, succinic acid or malonic acid, or by an organic acid, It is a salt of an amino group formed by other methods known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipine, alginate, and ascorbate. Aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate Camphorate, camphor sulfonate, citrate, cyclopentanpropyl Onates, digluconates, dodecyl sulfates, ethanesulfons, formates, fumarates , glucoheptanoate, glycerophosphate, gluconate, hemisulfate, heptanoate, Hexane salts, hydroiodide, 2-hydroxyethanesulfonates, Ctobionate, lactate, laurate, lauryl sulfate, malate, maleate, Malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate Oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 - Phenylenpropionate, phosphate, picrate, pivalate, propionate, s Thearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfone Examples include salts derived from appropriate bases, such as undecanoates and valers. , alkali metals, alkaline earth metals, ammonium, and N + (C1~C4 alkyl)4 - Salt It can be produced. Typical alkali or alkaline earth metal salts include sodium, lithium, Potassium, calcium, and magnesium are examples. Further pharmaceutically acceptable salts are also available. As appropriate, non-toxic ammonium, quaternary ammonium, and hara Idoids, hydroxides, carboxylic acids, sulfuric acids, phosphoric acids, nitric acids, lower alkyl sulfonic acids and aryl compounds. Examples include amine cations formed using counterions such as sulfonic acid.

[0019] The term "polymer" is given its usual meaning in this field, namely, covalent bonds. It is a molecular structure containing one or more repeating units (monomers) linked together by a compound. The repeating units are They may all be identical, or in some cases, there may be more than one type of iteration. The units may be present in the polymer. In one embodiment, the polymer is naturally occurring In some embodiments, polymers are synthetic (i.e., they do not exist in nature). In some embodiments, the polymer for use according to this disclosure is a polypeptide. In some embodiments, the polymers for use according to this disclosure are not nucleic acids.

[0020] The term "bioadhesive" refers to a substance that adheres to a target surface, such as a tissue surface. It refers to a biocompatible agent. In some embodiments, the bioadhesive is applied to a target surface, for example It can bind to the tissue surface and, for example, be retained on the target surface for a certain period of time. In some embodiments, the bio-adhesive may be biodegradable. Furthermore, bioadhesives may be natural agents, which can be obtained by isolation or synthesis. It may be prepared or obtained; in some embodiments, the bioadhesive is It may be a non-natural agent, for example, made by human hands (for example, as understood by those skilled in the art) (In a manner that depends on the agent, through processing, synthesis, and / or recombinant production) It may be designed and / or manufactured. In some specific embodiments, it is raw Body adhesives may be polymeric materials or may contain polymeric materials. For example, multiple polymers It may consist of nomers or contain them (such as sugars). Specific examples As a bio-adhesive, for example, cyanoacrylate (Dermabond, 2-octyl cyanoacrylate) Rate; Indermil, n-butyl-2-cyanoacrylate; Histoacryl and Histoacryl Blue n-butyl-2-cyanoacrylate), albumin and glutaraldehyde (BioGlue (commercial (Market), bovine serum albumin and 10% glutaraldehyde), fibrin glue (Tisseel (trademark)) , human pooled plasma fibrinogen and thrombin; Evicel®, human pool Processed plasma fibrinogen and thrombin; Vitagel®, autologous plasma fibrinogen Linogen and thrombin; Cryoseal® system, autologous plasma fibrinogen (and thrombin), cross-linked with formaldehyde and / or glutaraldehyde Gelatin and / or resorcinol, polysaccharide-based adhesives (gelatin, collagen, etc.) (Kistran, chitosan, alginate), PEG, acrylate, polyamine, or ureta N derivatives (a variety of FDA-approved agents such as isocyanate-terminated prepolymers, and / or a combination thereof. ies and Applications of Tissue Bioadhesives” Macromol Biosci 13:271-288 (2013). Examples of bioadhesives and other materials known in the art, as described in [reference], are used herein. It can be used for the purposes of the methods described. In some embodiments, biocontact The adhesive may be a biodegradable bioadhesive. Examples of such biodegradable bioadhesives include: These are not limited to, but include fibrin glue, gelatin-resorcinol-formaldehyde / Glutaraldehyde glue, poly(ethylene glycol) (PEG)-based hydrogel adhesive, Polysaccharide adhesives, polypeptide adhesives, polymeric adhesives, biomimetic bioadhesives, and Bhagat and Becker, "Degradable Adhesives for Surgery and Tissue Engineering" B Examples include those described in iomacromolecules 18: 3009-3039 (2017).

[0021] The term "crosslinking agent" refers to a substance that crosslinks one entity (e.g., one polymer chain) to another entity (e.g., another polymer chain). This refers to an agent that links to a M-chain. In some embodiments, it refers to the linkage between two entities (i.e., "Bridge" is a covalent bond, or includes one. In some embodiments, two real The connections between fields are either non-covalent associations or include such associations. For example, several In this embodiment, the connection between the two entities is either an ionic bond or an ionic interaction. or including the same. In some embodiments, the crosslinking agent is between the aldehyde and the amino group. These are small molecules (e.g., dialdehydes or genipines) that induce the formation of covalent bonds. In some embodiments, the crosslinking agent comprises a photosensitive functional group. The crosslinking agent contains pH-sensitive functional groups. In some embodiments, the crosslinking agent is heat-sensitive. Contains functional groups.

[0022] The term "solvate," when used herein, is understood in the art in which it is used. It has the meaning of being combined with a compound (which may be in the form of a salt of the compound, for example) and one or more solutions. This refers to aggregates with a medium atom or molecule. In some embodiments, the solvate is a liquid. In some embodiments, the solvate is in solid form (e.g., crystalline form). In some embodiments, the solvate in solid form can be isolated. The association between solvent atoms and compounds in a solvate is a non-covalent association. In this manner, such associations are hydrogen bonds, van der Waals interactions, or It is a combination of these, or includes them. In some embodiments, the atom is a solvent The solvents contained in the mixture are water, methanol, ethanol, acetic acid, DMSO, THF, and diethyl acetate. It may be one or more of the following, or may contain them. A suitable solvate is: It may be a pharmaceutically acceptable solvate; in some specific embodiments, the solvate is These are hydrates, ethanolates, or methanolates. In some embodiments, solvates This can be either a stoichiometric solvate or a non-stoichiometric solvate.

[0023] The term "hydrate," when used herein, is understood in the art in which it is used. It has the meaning of a compound (which may be in the form of a salt of the compound, for example) and one or more water molecules. This refers to aggregates of water molecules. Typically, the number of water molecules in the hydrate of a compound is the number of water molecules in the hydrate of the compound. The ratio is deterministic with respect to the number of molecules. Therefore, the hydrate of a compound is, for example, a general formula It can be expressed as R·x H2O, where R is the compound and x is a number greater than 0. A given compound can be, for example, a monohydrate (where x is 1), a lower hydrate (where x is greater than 0 and less than 1), and a more lower hydrate (where x is greater than 0 and less than 1). The values ​​are small, for example, hemihydrate (R·0.5 H2O) and polyhydrate (x is greater than 1). A number, including, for example, dihydrate (R·2 H2O) and hexahydrate (R·6 H2O)), more than one. It can form a hydrate of the following type.

[0024] The term "tautomer" or "of a tautomer" refers to a hydrogen atom undergoing at least one formal transformation. A transfer and at least one change in bond valence (e.g., from a single bond to a double bond, from a triple bond to...) This refers to a compound consisting of two or more interconvertible bonds (or vice versa). The exact ratio of mutants depends on several factors, including temperature, solvent, and pH. (Tautomerism) Immunization (i.e., the reaction that provides tautomer pairs) can be catalyzed by an acid or a base. Exemplary tautomerizations include keto to enol, amide to imide, and lactam. Intermutation from lactim, from enamine to imine, and from enamine to (different enamines) Isomerization is one example.

[0025] Furthermore, even if compounds have the same molecular formula, the properties or arrangement of their atomic bonds may differ. It is understandable that substances with different spatial arrangements of their atoms are called "isomers." It should be done. "Isomers" are different in the spatial arrangement of those atoms. It is referred to as "body".

[0026] The term "polymorphism" refers to the crystalline form of a compound (or its salt, hydrate, or solvate). Many compounds can take on diverse and different crystalline forms (i.e., different polymorphisms). Typically, such different crystal forms result in different X-ray diffraction patterns and infrared spectra. It possesses and / or melting point, density, hardness, crystal shape, optical properties, electrical properties, and stability. It may differ in some or all of its properties, such as solubility, solubility, and bioavailability. The recrystallization solvent, crystallization rate, storage temperature, and other factors can affect the crystallization process, resulting in a single crystalline form. The given preparation can be controlled. The diverse polymorphism of the compound is typically due to various conditions. It can be prepared by crystallization under the following conditions.

[0027] The term "cocrystal" refers to a crystal structure consisting of at least two constituent components. In this, the cocrystal contains the compound of interest (e.g., those disclosed herein), and One or more other constituent components, such as one or more atoms, ions, or molecules (e.g., solvent molecules). It includes. In one embodiment, the cocrystal contains the compound of interest and one or more solvent molecules. In one embodiment, the cocrystal comprises the compound of interest and one or more acids or bases.

[0028] The term "prodrug" refers to a form of active compound that is obtained through solvolysis or physiological processes. One or more compounds that are removed under scientific conditions, resulting in the release of active compounds. This refers to substances containing a cleavable group. Examples of prodrug forms are limited to these. Examples include choline ester derivatives and N-alkylmorpholine esters. In some embodiments, the prodrug is, for example, a hydrophilic acid and a suitable alcohol. Esters are prepared by the reaction of a hydrophilic compound with a substituted or unsubstituted amine. Further preparations of amides, acid anhydrides, or mixed anhydrides known in the art are available. It may be an acid derivative such as the one derived from the pendant-like acidic group on the target compound. Pure aliphatic or aromatic esters, amides, and anhydrides are special prodrug forms. This is an example. In some cases, (acyloxy)alkyl ester or ((alco Prepare double ester-type prodrugs such as xycarbonyl(oxy)alkyl esters. This may be desirable. The target compound may be C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 Alkinyl, aryl, C7~C 12 Substituting aryls, and C7~C 12 Arylalkyl esters .

[0029] The "targets" to whom administration is intended are not limited to these, but include humans (i.e., any Male or female of an age group, for example, child subjects (e.g., infants, children, adolescents) or adult subjects. Elephants (for example, young adults, middle-aged adults, or elderly adults), and / or non-human animals For example, mammals (for example, primates (for example, crab-eating macaques, rhesus macaques); cattle, pigs) , domestic animals such as horses, sheep, goats, cats and / or dogs; and / or birds (e.g.) Examples include chickens, ducks, geese and / or turkeys. In this context, an animal is a mammal (for example, at any stage of development). In that embodiment, animals (e.g., non-human animals) are transgenic or genetically modified. It may also be an animal that has been treated. In some embodiments, the subject is a tumor resection subject, for example, a recently The subjects are those who have undergone tumor resection. In some embodiments, the subjects who have undergone tumor resection are as specified herein. Less than 72 hours (e.g., 48 hours) before receiving the drug delivery composition or device described herein. During a period of less than 24 hours, less than 12 hours, less than 6 hours, or shorter than that, The subjects are those who have undergone tumor resection. In some embodiments, the subjects who have undergone tumor resection are as specified herein. Within 48 hours prior to receiving the drug delivery composition or device described herein, tumor resection The subject is the one who underwent removal. In some embodiments, the tumor resection subject is described herein. If the tumor is resected within 24 hours prior to receiving the drug delivery composition or device on which it is listed, The target is a digit. In some embodiments, the target for tumor resection is as described herein. In patients who have undergone tumor resection less than 12 hours prior to receiving the drug delivery composition or device, It's an elephant.

[0030] The term "biological sample" refers to tissue samples (such as tissue sections and tissue needle biopsies); cell samples (for example) If obtained by cytological smear (such as a Pap smear or blood smear) or microscopic dissection. Cellular samples; whole organism samples (such as yeast or bacterial samples); or cell fractions, flora Organelles or cell components (by lysing cells and separating their components by centrifugation or other methods) This refers to any sample, including those obtained by further separation. Examples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucous membranes, tears, Sweat, pus, biopsy tissue (e.g., obtained by surgical biopsy or needle biopsy), nipple aspiration Liquid, breast milk, vaginal fluid, saliva, swab (such as an oral swab), or raw material derived from the first biological sample. Any material containing body molecules is an example.

[0031] The terms “administer,” “to administer,” or “administer” are used in this specification. Drug delivery compositions that can be implanted, absorbed, digested, or injected This refers to inhaling it or introducing it by another means.

[0032] The terms “treatment,” “to treat,” and “to treat” are used in this specification. "Pathological condition" (e.g., a disease, disorder or one of its signs or symptoms) To reverse, alleviate, delay the onset of, or slow down the condition. This refers to inhibiting one or more signs or symptoms. In some embodiments, the treatment involves inhibiting one or more signs or symptoms. It may be administered after the onset or observation of symptoms. Treatment may also be administered when the symptoms resolve. Afterwards, for example, to delay or prevent recurrence and / or spread, You may continue.

[0033] The terms "condition," "disease," and "disability" are interchangeable.

[0034] "Effective dose" refers to the amount of substance that elicits the desired biological response, for example, the amount of substance that the subject is suffering from. This refers to a sufficient amount to treat a potentially problematic condition. Therefore, the effective amount of the drug delivery composition is the desired biological endpoint, and the therapeutic agent in the composition. It varies depending on factors such as pharmacokinetics, the condition being treated, the age and health of the subject. To obtain. An effective dose includes therapeutic and prophylactic treatments. For example, treating cancer. In this context, the effective dose is one that prevents tumor regrowth, reduces tumor burden, or controls tumor growth. It can halt growth or spread. Those skilled in the art will know that an effective amount is contained in a single dosage form. You will understand that this is not necessary. Rather, an effective dose may potentially have a long-term effect (e.g.) This may include administering multiple doses (for example, according to the administration regimen).

[0035] "Therapeutic dose" refers to an amount sufficient to provide a therapeutic benefit in the treatment of a condition. This therapeutic benefit, for example, refers to one or more characteristics or symptoms associated with the condition in question. Even if it is a decrease in frequency and / or severity, and / or a delay in its onset, These may also be included. A therapeutically effective dose is the amount administered alone or in combination with other therapeutic agents. This refers to the amount of therapeutic agent that provides therapeutic benefit in the treatment of a condition. (Term: "Therapeutic effective dose") This may improve the overall treatment, alleviate or avoid the symptoms or causes of the condition, or otherwise It includes an amount that enhances the therapeutic effect of the therapeutic agent. Those skilled in the art will know that the therapeutic effective dose is a single dose form. You will understand that it does not need to be included in the package. Rather, an effective dose is a potential This may include administering multiple doses over time (e.g., according to a dosing regimen).

[0036] "Preventive effective dose" refers to the amount of a substance needed to prevent a certain condition (for example, one or more symptoms of a certain condition or The onset or recurrence of the characteristic, for example, is not expected to be absent with the dose in question. A sufficient amount (to significantly delay detection so that it will not be detected even at the time it is measured) The preventive effective amount of the composition is the amount used to prevent the condition, either alone or in combination with other therapeutic agents. In prevention, this refers to the amount of therapeutic agent that provides a preventive benefit. The term "therapeutic effective dose" means: It may include an amount that improves overall prevention or enhances the preventive efficacy of another preventive agent. They will understand that the prophylactic effective dose does not need to be contained in a single dosage form. Rather, an effective dose is potentially a time-dependent (e.g., according to a dosing regimen) multiple doses. This may include the administration of [a specific drug].

[0037] "Proliferative disorders" refer to abnormal proliferation (growth) or expansion due to the proliferation (multiplication) of cells. This refers to diseases caused by extension (Walker, Cambridge Dictionary of Biology). (Cambridge University Press: Cambridge, UK, 1990). Proliferative disorders may be associated with the following: ru: 1) Pathological proliferation of cells that are normally in a quiescent state; 2) Pathology of cells moving away from their normal location. 3) Translocation of neoplastic cells (e.g., metastasis of neoplastic cells); 4) Translocation of matrix metalloproteinases and other substances Pathological expression of protein-degrading enzymes (e.g., collagenase, gelatinase and elastinase) Ze); or 4) Pathological neovascularization such as that in proliferative retinopathy and tumor metastases. Example Typical proliferative disorders include cancer (i.e., "malignant neoplasms"), benign neoplasms, angiogenesis, and These include diseases related to angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases. It can be done.

[0038] The terms “neoplasm” and “tumor” are used interchangeably herein and refer to an abnormal mass of tissue. This refers to a situation where the proliferation of the mass inhibits or does not coordinate with the proliferation of normal tissue. A neoplasm or tumor can be "benign" or "malignant" depending on the following characteristics: The degree of vesicular differentiation (including morphology and function), rate of proliferation, local invasion, and metastasis. "Benign neoplasms" "These tumors" are generally well-differentiated, have characteristically slower growth than malignant tumors, and originate from the original site. It remains localized. In addition, benign neoplasms infiltrate, invade, These do not have the ability to metastasize to distal sites. Examples of benign neoplasms are limited to these. However, lipoma, chondroma, adenoma, acrochordon, senile angioma, seborrheic keratosis, mole, And sebaceous gland hyperplasia is another example. In some cases, certain "benign" tumors are later This can lead to malignant neoplasms, and this is due to further genetic inheritance in subpopulations of neoplastic cells in tumors. These tumors can arise from changes in the body and are referred to as "premalignant neoplasms." One example of such a thing is a teratoma. In contrast, "malignant neoplasms" are generally poorly differentiated (regressed). Characterized by rapid growth, accompanied by formation, progressive invasion, invasion, and destruction of surrounding tissues. Furthermore, malignant neoplasms generally have the ability to metastasize to distal sites.

[0039] The terms “metastasis,” “metastatic,” or “metastatic” refer to a tumor that is separated from the primary or original tumor. This refers to the spread or migration of cancer cells to organs or tissues, typically from the primary or original site. The presence of a tumor histological type called "secondary tumor" or "secondary cell mass," and secondary (metastatic) The absence of a "secondary tumor" or "secondary cell mass" in the organ or tissue where the tumor is located indicates the same It is possible to determine this. For example, prostate cancer that has metastasized to the bone is called metastatic prostate cancer, and it can cause bone tissue to smell. It includes cancerous prostate cancer cells that proliferate.

[0040] The term "cancer" refers to malignant neoplasms (Stedman's Medical Dictionary, 25th edition; Hens). (YL edited by Williams & Wilkins: Philadelphia, 1990). In the context of some aspects of this disclosure Of particular interest are the treatments that kill and / or remove cells (e.g., surgical excision, and Treatment by / or treatment with certain chemotherapy agents, such as cytotoxic agents. It is a type of cancer. In some embodiments, the cancer treated by this disclosure is surgically resected. Those that have been treated (i.e., those in which at least one tumor has been surgically removed) In some embodiments, cancers treated by this disclosure are those for which resection is the standard treatment. In some embodiments, the cancers treated by this disclosure are metastatic. In one aspect, one or more of the following can be cited as exemplary cancers. Acoustic neuroma; adenocarcinoma; adrenal carcinoma; anal carcinoma; angiosarcoma (e.g., lymphangiosarcoma) lymphangioendotheliosarcoma, hemangiosarcoma; parasites Tumor cancer; benign monoclonal immunoglobulinemia; biliary tract cancer (e.g., cholangiocarcinoma); cholangiocarcinoma; bladder Bladder cancer; bone cancer; breast cancer (e.g., adenocarcinoma of the chest, papillary carcinoma of the chest, breast cancer, medullary carcinoma of the chest); brain cancer (e.g.) For example, meningioma, glioblastoma, glioma (e.g., astrocytoma, oligodendroglioma, medulloblastoma) Bronchial cancer; carcinoid tumors; cardiac tumors; cervical cancer (e.g., adenocarcinoma of the cervix); choriocarcinoma Chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue Cancer; epithelial carcinoma; ductal carcinoma in situ; ependymoma; episarcoma (for example, Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma; child Endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma); -ing's sarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma); familial hypereosinophilia; bile duct Cystic carcinoma; gastric carcinoma (e.g., adenocarcinoma of the stomach); gastrointestinal stromal tumor (GIST); germ cell carcinoma; head and neck cancer (e.g., Squamous cell carcinoma of the head and neck, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer) Cancer, nasopharyngeal cancer, oropharyngeal cancer); hematopoietic cancer (e.g., acute lymphoblastic leukemia (ALL) (e.g., B cell carcinoma) Leukemias such as cystic ALL and T-cell ALL, acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML) , chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CL) L) (e.g., B-cell CLL, T-cell CLL); lymphoma, e.g., Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL, e.g., diffuse lymphoma) 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), peripheral Marginal zone B-cell lymphoma (e.g., intramucosal lymphoid tissue (MALT) lymphoma, nodular marginal zone B-cell lymphoma) (B-cell lymphoma of the splenic marginal zone), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymph Plasma cell lymphoma (i.e., Waldenström macroglobulinemia), hairy cystitis Leukemia leukemia (HCL), immunoblastic large cell lymphoma, precursor B lymphoblastic lymphoma and primary Central nervous system (CNS) lymphoma; and T-cell NHL, e.g., precursor T-lymphoblastic lymphoma / white lymphoma. Blood disorders, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides) Sézary syndrome, angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma. Parkinson's disease; a mixture of one or more leukemias / lymphomas as described above; multiple myeloma; heavy chain disease (for example) Alpha chain disease, gamma chain disease, muon chain disease; hemangioblastoma; histiocytosis; hypopharyngeal cancer; inflammation Myofibroblastic tumors; immune cell amyloidosis; kidney cancer (e.g., nephroblastoma, also known as viroma). Musculoskeletal tumors, renal cell carcinoma; liver cancer (e.g., hepatocellular carcinoma (HCC), malignant hepatoma); lung cancer (e.g., , bronchogenic lung cancer, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (L MS; mastocytosis (e.g., systemic mastocytosis); melanoma; midline tract carcinoma a); Multiple endocrine neoplasia syndrome; Myocarcinoma; Myelodysplastic syndrome (MDS); Mesothelioma; Myeloproliferative disorder ( MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), primary myelofibrosis (agno) Myelofibrosis (AMM), also known as chronic idiopathic myelofibrosis, chronic bone Myelin leukemia (CML), chronic neutrophilic leukemia (CNL), eosinophilic syndrome (HES); nasopharyngeal carcinoma; neurological Blastoma; neurofibroma (e.g., neurofibromatosis type 1 or 2, schwannoma); neuroendocrine carcinoma (For example, pancreatic gastrointestinal neuroendocrine tumors (GEP-NETs), carcinoid tumors); osteosarcoma (for example, bone cancer) ); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonic carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., Pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), islet cell tumor; parathyroid carcinoma; papillary adenocarcinoma; genital Stem cancer (e.g., Paget's disease of the penis and scrotum); pharyngeal cancer; pineal gland tumor; pituitary cancer; pleuropulmonary blastoma Cell tumor; primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndrome; carcinoma in situ Prostate cancer (e.g., adenocarcinoma of the prostate); rectal cancer; rhabdomyosarcoma; retinoblastoma; salivary gland cancer; skin cancer Skin cancer (e.g., squamous cell carcinoma (SCC), keratinized acanthoma (KA), melanoma, basal cell carcinoma (BCC)); small intestine Cancer (e.g., appendiceal cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant terminal cancer) Peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma; sebaceous gland carcinoma; gastric cancer; small intestine cancer; sweat gland Cancer of the body; synovial tumor; testicular cancer (e.g., seminoma, embryonal testicular cancer); thymic cancer; thyroid cancer (e.g., , papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma); urethral cancer; uterine cancer; vaginal cancer; and Vulvar cancer (for example, Paget's disease of the vulva).

[0041] The term "immunotherapy" refers to inducing, enhancing, or suppressing an immune response. This refers to therapeutic agents that promote the treatment of a disease by inducing or amplifying an immune response. Immunotherapy designed to reduce the immune response is classified as activated immunotherapy, while immunotherapy designed to reduce the immune response. Immunotherapy that either suppresses or inhibits this is classified as suppressive immunotherapy. While not exactly the same, it is typically a biotherapy. Many immunotherapies treat cancer. These are used for the purpose of monoclonal antibodies and adoptive cell transfer. Includes cytokines, chemokines, vaccines, small molecule inhibitors, and small molecule agonists. For example, useful immunotherapies include, but are not limited to, type I interferon. Inducing factors, interferon, interferon gene stimulating factor (STING) agonist, TLR 7 / 8 agonist, IL-15 superagonist, anti-PD-1 antibody, anti-CD137 antibody, and anti-CTLA-4 Antibodies can be cited.

[0042] The terms "biologic," "biopharmaceutical," and "biopharmaceutical" are used. "Medicinal products (biological products)" include vaccines, blood and blood components, and allergens. NICS refers to a wide range of products including somatic cells, gene therapy agents, tissues, nucleic acids, and proteins. Biopharmaceuticals are sugars, proteins, nucleic acids, or complex combinations of these substances. It may contain, or it may be a living entity such as cells and tissues. Bio-made The agents may be isolated from a variety of natural sources (e.g., human, animal, microorganism), and It can be manufactured by / or by biotechnological methods and / or other techniques.

[0043] The term "antibody" refers to a functional component of serum, and is often a collection of molecules (antibodies are also...). (As immunoglobulins), or as a single molecule (antibody molecule or immunoglobulin molecule) And so it is mentioned. Antibodies bind to specific antigen-determining factors (antigens or epitopes of antigens). It can either do so or react with it, which then leads to the immunological effector mechanism This leads to induction. Individual antibodies are usually considered to be monospecific, and the composition of antibodies is Even if monoclonal (i.e., consisting of the same antibody molecule), polyclonal (i.e., And, the same or different epitopes on the same antigen or on different antigens that can be distinguished It may consist of two or more different antibodies that react with each other. It has a unique structure that allows it to specifically bind to the corresponding antigen, and all natural antimicrobial The body has the same overall basic structure, consisting of two identical light chains and two identical heavy chains. They are also collectively known as immunoglobulins. Antibodies are human or non-human (e.g., Even if it originates from rodents such as mice, dogs, camels, etc. (for example, human or non-human) (Even if it has a sequence that originally arose in human cells or organisms), or for example, Based on human or non-human antibodies (or, in some embodiments, their antigen-binding moieties) Antibodies that have been chimeric, humanized, reshaped, or reformatted. It may also include this.

[0044] In some aspects, as will be clear from the context, the term “antibody” refers to the following: When used in writing, it includes a format containing the antibody's epitope-binding sequence, The format is, for example, chimeric and / or single-chain antibodies (e.g., nanobodies or This refers to antibodies such as Fcab, as well as Fab, Fv fragments, or single-chain Fv (scFv) fragments. This includes binding fragments, as well as multimeric forms such as dimeric IgA molecules or pentavalent IgM molecules. Also included are bispecific antibodies, bispecific T-cell inducing antibodies (BiTEs), and immunomobilization antibodies. Cancer monoclonal T cell receptor (ImmTAC), dual-affinity retargeting re-targeting: DART); alternative scaffold or antibody mimetic (e.g., an Chikarin, FN3 Monobody, DARPins, Affibodies, Affilins, Affimers, Affitins, Al phabodies, Avimers, Fynomers, Im7, VLR, VNAR, Trimab, CrossMab, Trident); Nanobo D, binanobody, F(ab')2, Fab', di-sdFv, single-domain antibody Includes trifunctional antibodies, diabodies, and minibodies.

[0045] The terms "small molecule" or "small molecule therapeutic agent" refer to molecules that are naturally occurring or artificially produced. This refers to molecules with relatively low molecular weight, whether or not they were synthesized (for example, through chemical synthesis). Typically, small molecules are organic compounds (i.e., they contain carbon). Small molecules are complex. A number of carbon-carbon bonds, stereocenters, and other functional groups (e.g., amine, hydroxyl, carbohydrate). It may also contain bonyl rings and heterocyclic rings. In one embodiment, the molecular weight of the small molecule These are approximately 1,000 g / mol or less, approximately 900 g / mol or less, approximately 800 g / mol or less, approximately 700 g / mol or less, and approximately 600 g / mol. Below are approximately 500 g / mol or less, approximately 400 g / mol or less, approximately 300 g / mol or less, approximately 200 g / mol or less, or approximately 10 It is 0 g / mol or less. In one embodiment, the molecular weight of the small molecule is at least about 100 g / mol, and less At least about 200 g / mol, at least about 300 g / mol, at least about 400 g / mol, at least about 500 g / m³ ol, at least about 600 g / mol, at least about 700 g / mol, at least about 800 g / mol, or less It is at least about 900 g / mol, or at least about 1,000 g / mol. Combinations of the above ranges (for example) For example, it is at least about 200 g / mol, and also about 500 g / mol or less. In this context, small molecules are therapeutic agents such as drugs (for example, according to the Code of Federal Regulations (CFR)). (Molecules approved by the U.S. Food and Drug Administration, such as those provided.) Small molecules also contain one or more It may form complexes with metal atoms and / or metal ions. In this example, small molecules They are also referred to as "organic small molecules." Preferred small molecules are biologically active agents. It is present and has biological effects in animals, preferably mammals, and more preferably humans. These are small molecules, but are not limited to these, and include radionuclides and imaging. Examples include agents. In one embodiment, the small molecule is a drug. Preferably, not necessarily However, drugs are subject to the regulations of the appropriate government agency or regulatory authority regarding their use in humans or animals. It is already considered safe and effective for human use. Drugs approved by the FDA are subject to 21 C.F. §§3, which is incorporated herein by reference. Listed below in sections 30.5, 331-361, and 440-460: Drugs for veterinary use are specified in this document. Listed in reference in the book, according to 21st century FR §§500-589. All listed The pharmaceutical product described is considered acceptable for use according to the present invention.

[0046] The term "therapeutic agent" refers to an agent having one or more therapeutic properties, which is desired, and is usually available. It refers to something that produces a beneficial effect. For example, a therapeutic agent either treats or alleviates a disease. and / or prevent this. In some embodiments, the therapeutic agent is a biopharmaceutical, small It may be a molecule, a combination thereof, or may contain such a molecule.

[0047] The term "chemotherapeutic agent" refers to a substance known to be usable in chemotherapy for cancer. It refers to a therapeutic agent.

[0048] The term "targeted agent" refers to a specific agent involved in the growth, progression, and spread of cancer. Anticancer drugs block the growth and spread of cancer by interfering with molecules ("molecular targets"). This refers to targeted drugs. Targeted drugs are sometimes also called "targeted cancer treatment agents," "molecular targeted drugs," or "molecular targeted therapy agents." This is also called "precision medicine." Targeted drugs act on specific molecular targets associated with cancer. However, many chemotherapy drugs act on all rapidly dividing cells (for example). It differs from standard chemotherapy in that it is used regardless of whether the cells are cancerous or not. Targeted agents are strategically selected or designed to interact with those targets, but on the other hand... Many standard chemotherapy regimens are identified as those that kill cells.

[0049] The term "biomaterial" refers to inducing an unacceptable reaction (according to sound medical judgment). It is not that it can be administered to a subject for medical purposes (e.g., treatment, diagnosis). It refers to biocompatible substances characterized by... It may be induced or synthesized. In some embodiments, the biomaterial is in the form of a gel. It may also be in the form of an injectable form. In some embodiments, the biomaterial is an injectable form It may also be in a mat. For example, biomaterials may be in situ (for example, on the subject) It may contain precursor components of the gel to be formed (after administration).

[0050] The term "hydrogel" refers to a material formed from a network of hydrophilic polymer chains. It refers to a material, and is sometimes found as a colloidal gel in which the aqueous phase is the dispersion medium. In this context, hydrogels are highly absorbent (for example, they absorb more than 90% of water). A natural or synthetic polymer network that can absorb and / or retain nutrients. In some embodiments, hydrogels, for example due to their high water content, It possesses a degree of flexibility similar to that of natural tissues.

[0051] The terms "transplantable," "transplant," "transplanting," and "to transplant" are typically used in the following contexts: This involves using general surgical methods to deliver the drug delivery composition to a specific location (sentinel line) in the target. This refers to placing the device within the tumor resection site in a lymph node, for example.

[0052] The term "biocompatibility" means that the material is substantially non-biogenic in the in vivo environment of its intended use. Toxicity is not substantially rejected by the patient's physiological system (i.e., non-antigenic) This refers to a certain material. This means that a certain material is an International Organization for Standardization (ISO) standard number 10993 and / or United States Pharmacopeia (USP) 23 and / or U.S. Food and Drug Administration (FDA) Blue Book Memorandum Document number G95-1, title "Use of International Standard ISO-10993, Biological Evaluation Biocompatibility as described in "n of Medical Devices Part-1: Evaluation and Testing" This can be measured by the ability to pass sex tests. Typically, these tests are, The toxicity, infectivity, pyrogenicity, irritating ability, reactivity, hemolytic activity, carcinogenicity, and / or Alternatively, immunogenicity is measured. Biocompatible structures or materials are introduced in the majority of patients. In general, it is a mild, transient inflammation typically associated with surgical procedures or the implantation of foreign objects into the body. A distinguished biological reaction is one that is unnecessarily harmful, long-lasting, or progressively increasing. It does not provoke a response or reaction.

[0053] The term "antagonist" means (i) reducing or eliminating the effect of one or more of another agents. (ii) to suppress; and / or (ii) to reduce or suppress one or more biological events. It refers to an agent that controls something. In some aspects, an antagonist is one of the agents it targets. The level and / or activity of the above agent can be reduced. In various embodiments, Antagonists are, for example, small molecules, polypeptides, nucleic acids, and carbohydrates that exhibit appropriate antagonistic activity. , or agents of a diverse chemical class, including lipids, metals, and / or other entities, This may also be included. The antagonist is direct (in that case, it is against its target) (Whether it exerts its effect directly) or indirectly (in which case it is connected to its target) Other than matching: for example, modifying the target so that its level or activity is altered. It may also exert its influence by interacting with factors. In this context, an antagonist is a receptor antagonist, such as an agonist. Rather than activating the body, it binds to receptors and blocks them, thereby preventing biological responses. This may be a receptor ligand or drug that blocks or weakens the receptor.

[0054] The term "agonist" means (i) an agent that enhances or induces the effect of one or more other agents. (ii) to increase or induce one or more biological events It refers to an agent that targets one or more agents. In some embodiments, an agonist is an agent that targets one or more agents. The level and / or activity may be increased. In various embodiments, agonists, for example, Small molecules, polypeptides, nucleic acids, carbohydrates, lipids, metals, and / or suitable agonists The agents may be a diverse chemical class containing other entities that exhibit the same effect, or may include such agents. That's good too. An agonist is direct (in this case, it directly targets its target) Even if it exerts an effect (in this case, it is by binding to its target), it is indirect (in this case, by binding to its target). In addition to the above; for example, control of the target so that the target level or activity is modified. (It may exert its influence by interacting with factors.) Partial agonist In the presence of a complete agonist, it acts upon its target and / or its regulators. It competes with interacting complete agonists, and thereby is observed only by complete agonists. Compared to the above, (i) a decrease in the effect of one or more other agents, and / or (ii) one or more Acting as a competitive antagonist by reducing physical events. It is possible.

[0055] The term "inhibit" or "block" refers to the level (e.g., expression level) of a target (e.g., p38 MAPK). Regarding the regulation of (and / or activity), it is not limited to overall inhibition only. In some embodiments, partial inhibition or relative reduction falls within the scope of the term "inhibition". It is included within. In some embodiments, the term refers to the level of the target (e.g., p38 MAPK) For example, the initial or other appropriate reference level of expression and / or activity (this is an example) (which may be the target baseline level) is more reproducible and / or statistically significant than , refers to a decrease to a low level. In some aspects, the term refers to the target level ( For example, the initial level of expression and / or activity (this is, for example, the baseline level of the target) Less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10% (OK) Full, 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% to levels of less than, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% indicates a decrease.

[0056] 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 exerts its effect directly on its target, for example by binding to the target); in some embodiments the inhibitor may act indirectly (in which case it interacts with a regulator of the target and / or modifies it in some other way so as to cause a decrease in the level and / or activity of the target). In some embodiments the inhibitor is one whose presence or level correlates with a decreased target level or activity as compared to a particular reference level or activity (e.g., that observed under appropriate reference conditions such as the presence of a known inhibitor, or the absence of an inhibitor disclosed herein). The term "inhibitor of an inflammation-inducing pathway" as used herein, in some embodiments refers to an agent that, in some embodiments, prevents the recruitment of immunosuppressive cells or prevents acute inflammation. Such acute inflammation and / or recruitment of immunosuppressive cells can occur after local trauma (including that caused by surgery). In some embodiments, an inhibitor of an inflammation-inducing pathway, for example, for example, an inflammation-inducing cytokine (e.g., TNF-alpha, IL-

[0057] 1, etc.).​​​​​​​ Production of 1β and IL-6, increased activity and / or proliferation of Th1 cells, recruitment of myeloid cells, etc. It may inhibit inflammation-inducing immune responses, including those related to [specific immune responses].

[0058] The term "pro-inflammatory immune response," as used herein, means, for example, pro-inflammatory immune response. Production of cytokines (e.g., TNF-alpha, IL-1β, and IL-6), and activation of Th1 cells. This refers to an immune response that induces inflammation, including enlargement and / or proliferation, and recruitment of myeloid cells. In some ways, pro-inflammatory immune responses are among the acute and chronic inflammations. It may be one or both of these, or it may include them.

[0059] The term "activator of the innate immune response" refers to an agent that activates the innate immune system. Sexualization helps to initiate an inflammatory response and / or induce an adaptive immune response. It can stimulate the expression of molecules that cause antigen-specific acquired immunity to develop. Activation of the immune system involves cytokine production, proliferation, and survival, as well as antigen presentation and resistance. T cell primin expression improved by enhancing the expression of co-stimulatory molecules by proto-presenting cells It could bring about a problem.

[0060] The term "activator of adaptive immune response" refers to an agent that activates the adaptive immune system. Sexualization occurs by neutralizing inhibitory immune checkpoints or by inducing costimulatory receptors. This leads to a helper and / or against immunogenic antigens ultimately expressed by cancer cells. This induces an effector T cell response, producing a population of memory B cells and / or T cells. This allows for the restoration of antitumor function. In one embodiment, it activates the adaptive immune response. Factors include the regulation of adaptive immune responses and / or leukocyte transport.

[0061] The term "modifier of macrophage effector function" refers to the effector function of macrophages. Activates processor function or is derived from immunosuppressive macrophages or macrophages. This refers to agents that deplete suppressor cells. Such enhancement affects macrophages and myeloid cells. It is possible to kinetically activate the constituent components and destroy the tumor and its interstitial tissue, including tumor vascular structures. Macrophages secrete antitumor cytokines and / or phagocytose (antibody-dependent). It can be induced to perform (including phagocytosis of living cells).

[0062] As used herein, the terms "sustained release" and "long-term release" are used interchangeably. "Extended release" is an equivalent term. The compositions and devices of this disclosure The therapeutic agent can be released over a period of time. The term "sustained" "Extended" means that one or more therapeutic agents are administered over a time period ranging from 5 minutes to several months. In this context, it may mean that it is released from a biomaterial. In one embodiment, one or more Less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30% of the therapeutic agent. Less than 20%, less than 10%, less than 5%, or less than 1% for 4 weeks, 3 weeks, 2 weeks, 10 days, or 7 days. 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, 18 hours, 12 hours, 8 hours, 6 hours, 4 hours , for periods of 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, 15 minutes, 10 minutes, or 5 minutes It is released from the biomaterial over a certain period. In one embodiment, more than 99% of one or more therapeutic agents, 95% %, 90% or more, 80% or more, 70% or more, 60% or more, 50% or more, 40% or more, 30% or more, 20 % or more, 10% or more, 5% or more, or 1% or more is released from the biomaterial over a period of 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 and is released from the biomaterial over a period of time. In some embodiments, the degree of sustained or long-term release can be characterized in vitro or in vivo. For example, in some embodiments, the release kinetics can be tested in vitro by placing a composition comprising the biomaterial and a therapeutic agent (e.g., a p38 MAPK inhibitor) in an aqueous buffered solution (e.g., PBS at pH 7.4). In some embodiments, when a composition comprising the biomaterial and a therapeutic agent (e.g., a p38 MAPK inhibitor) is placed in an aqueous buffered solution (e.g., PBS at pH 7.4), 100% or less (e.g., 90% or less, 80% or less, 70% or less, 50% or less, or lower) of the therapeutic agent is released from the biomaterial within 3 hours. In some embodiments , the release kinetics can be tested in vivo by implanting a composition comprising the biomaterial and a therapeutic agent (e.g., a p38 MAPK inhibitor) into a target site (e.g., the mammary fat pad) of an animal subject (e.g., a mouse subject). In some embodiments, when a composition comprising the biomaterial and a therapeutic agent (e.g., a p38 MAPK inhibitor) is implanted into a target site (e.g., the mammary fat pad) of an animal subject (e.g., a mouse subject), 70% or less or lower (e.g., 60% or less or lower, 50% or less or lower, 40% or less or lower, 30% or less or lower) of the therapeutic agent is released from the biomaterial. In some embodiments, the release kinetics can be tested in vivo by implanting a composition comprising the biomaterial and a therapeutic agent (e.g., a p38 MAPK inhibitor) into a target site (e.g., the mammary fat pad) of an animal subject (e.g., a mouse subject). In some embodiments, when a composition comprising the biomaterial and a therapeutic agent (e.g., a p38 MAPK inhibitor) is implanted into a target site (e.g., the mammary fat pad) of an animal subject (e.g., a mouse subject), 70% or less or lower (e.g., 60% or less or lower, 50% or less or lower, 40% or less or lower, 30% or less or lower) of the therapeutic agent is released from the biomaterial. For example, 60% or less or lower, 50% or less or lower, 40% or less or lower, 30% or less (or lower levels) are released in vivo 8 hours after transplantation. [Brief explanation of the drawing]

[0063] [Figure 1] Figure 1 shows Kaplan-Meier curves for female BALB / cJ mice orthotopically inoculated with 4T1-Luc2 cells, whose tumors were surgically resected, and subsequently implanted with an exemplary drug delivery device containing a hydrogel without a p38 MAPK inhibitor (e.g., cross-linked hyaluronic acid hydrogel), or an exemplary drug delivery device containing a hydrogel (e.g., cross-linked hyaluronic acid) and a p38 MAP kinase inhibitor (e.g., rosmapimod).

[0064] [Figure 2] Figure 2 shows the Kaplan-Meier curves for female BALB / cJ mice orthotopically inoculated with 4T1-Luc2 cells, whose tumors were surgically excised, and subsequently implanted with either an exemplary drug delivery device containing a hydrogel without anti-IL-1β antibody (e.g., cross-linked hyaluronic acid hydrogel) or an exemplary drug delivery device containing a hydrogel (e.g., cross-linked hyaluronic acid) and an anti-IL-1β antibody (e.g., clone B122).

[0065] [Figure 3] Figure 3 shows the Kaplan-Meier curves for female BALB / cJ mice orthotopically inoculated with 4T1-Luc2 cells, whose tumors were surgically excised, and subsequently implanted with either an exemplary drug delivery device containing a hydrogel without anti-IL-6 antibody (e.g., cross-linked hyaluronic acid hydrogel) or an exemplary drug delivery device containing a hydrogel (e.g., cross-linked hyaluronic acid) and an anti-IL-6 antibody (e.g., clone MP5-20F3).

[0066] [Figure 4]Figure 4 is a schematic diagram illustrating the interrelationship of specific pro-inflammatory pathways, including p38 mitogen-activated protein kinase (MAPK) and COX-2. See Desai et al., "Mechanisms of Phytonutrient Modulation of Cyclooxygenase-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 recognize that pro-inflammatory signals, such as the cytokines TNF-α, IL-6, and / or IL-1β, can stimulate COX-2 transcription, for example, through activation of the MAPK pathway. For example, it has been established that IL-1β upregulates COX-2 expression through activation of the p38 MAPK pathway (Huang et al., "MAPK / ERK signal pathway involved expression of COX-2 and VEGF by IL-1beta induced in human endometriosis stomal cells in vitro," Int J Clin Exp Pathol, 6: 2129-2136 (2013) and Di Mari et al., "HETEs enhance IL-1-mediated COX-2 expression via augmentation of message stability in human colonic myofibroblasts," Am J Physiol-Gastrointest Liver Physiol., 293: 2092-2101 (2007)).

[0067] [Figure 5]Figure 5 is a schematic diagram illustrating how certain nonsteroidal anti-inflammatory drugs (NSAIDs) can act as cyclooxygenase (COX) inhibitors, including, for example, COX-1 and / or COX-2 inhibitors, and / or p38 MAPK inhibitors. See Esposito et al., "Non-steroidal anti-inflammatory drugs in Parkinson's disease," Experimental Neurology 205: 295-312 (2007). For example, in some embodiments, NSAIDs can inhibit or reduce the activity and / or levels of COX-1 and / or COX-2. In some embodiments, NSAIDs can inhibit or reduce the activation of the p38 MAPK pathway or its components, thereby reducing or inhibiting AP-1 activation.

[0068] [Figure 6] Figure 6 is a schematic diagram illustrating the interrelationship of specific pro-inflammatory pathways involving p38 mitogen-activated protein kinase (MAPK) and Wnt-β-catenin. See Bikkavilli et al., "p38 mitogen-activated protein kinase regulates canonical Wnt-β-catenin signaling by inactivation of GSK3β," Journal of Cell Science, 121: 3598-3607 (2008). Those skilled in the art familiar with such pathways will recognize that p38 MAPK can be activated by Wnt3a stimulation, and that such stimulation can be dependent on both G proteins and discibulds. P38 MAPK-specific inhibitors can reduce Wnt3a-induced β-catenin expression. Therefore, p38 MAPK plays a role in Wnt-β-catenin signaling, for example, by inactivating GSK3β and / or by acting downstream of discibulds. [Modes for carrying out the invention]

[0069] Detailed description of a certain aspect Provided herein are target sites of one or more immunomodulators (for example, tumors). They are removed, and / or cancer cells are treated, for example, by chemotherapy or radiation. By limiting delivery to the site of injury or death, the effect of the immunomodulator can be controlled. This is a drug delivery composition and device that can concentrate the drug at the target site where it is needed. Such drug delivery systems may be particularly useful for treating cancer. Drug delivery compositions and The device may include biomaterials and inhibitors of inflammatory pathways. Furthermore, the drug delivery composition and device are made of biomaterials and p38 mitogen-activated protein Inhibitors of pro-inflammatory immune responses mediated by the protein kinase (MAPK) pathway (e.g., p38 MAPK) The drug delivery composition and device may contain an inhibitor. The drug delivery composition and device may contain a biomaterial, p38 mitogen. Inhibitors of pro-inflammatory immune responses mediated by the activated protein kinase (MAPK) pathway, The drug delivery composition and device may also contain activators of the innate immune response. Materials, inflammation mediated by the p38 mitogen-activated protein kinase (MAPK) pathway The formulation may also include inhibitors of the sexual immune response, activators of the innate immune response, and cytokines. The drug delivery composition and device are made from biomaterials, including p38 mitogen-activated protein kinases. Inhibitors of pro-inflammatory immune responses mediated by the MAPK pathway, and activators of innate immune responses. , and may also contain chemokines. The drug delivery composition and device may be one or more indications The drug delivery composition and device may further contain an activator of the immune response. Therapeutic agents (e.g., inhibitors of pro-inflammatory pathways, modifiers of macrophage effector function) It may further contain (a child or chemotherapy agent).

[0070] In some embodiments, therapeutic agents provided in drug delivery compositions and devices (e.g.) Immunomodulators, for example, are used to treat inflammation induced by surgical procedures such as surgical tumor resection (e.g., chronic inflammation). A unique tool for treating cancer, especially solid tumors, by mediating (sexual inflammation). This can provide a drug delivery composition and device in some embodiments. The therapeutic agents provided (e.g., immunomodulators) are induced by surgical procedures such as surgical tumor resection. It can inhibit the inflammation that is being induced (e.g., chronic inflammation). In some embodiments, the drug The therapeutic agent (e.g., immunomodulator) provided in the delivery composition and device is derived from myeloid cells. It can reduce or inhibit the activity of pressor cells (MDSCs). In one embodiment, therapeutic agents (e.g., immunotherapy) provided in drug delivery compositions and devices are provided in a drug delivery composition and device. These agents can reduce or inhibit the recruitment of immunosuppressive cells. In some embodiments, therapeutic agents provided in drug delivery compositions and devices (e.g.) Immunomodulators can reduce or inhibit acute inflammation. In that embodiment, the drug delivery composition and device are suitable for the innate immune response system and / or This may further contain one or more therapeutic agents (e.g., immunomodulators) that activate the immune response system. The compositions, devices, methods, systems, and kits provided in this specification also include cell administration. (e.g., adoptive cell transfer) or further constructs such as microparticles, peptides or tumor antigens This method is advantageous over existing methods in that it does not require the incorporation or presence of any components.

[0071] The drug delivery compositions and devices described herein are for perioperative settings. It is useful for treating cancer (e.g., solid tumors) in some embodiments. The composition and device are used in the area of ​​need for treatment in the subject requiring it. Immunotherapy agents can be delivered by implanting the device described herein. In some embodiments, the drug delivery compositions and devices are immunomodulatory agents. (For example, a p38 MAPK inhibitor) can be directly released to the site of tumor resection, and systemic administration can be repeated. Because it can be avoided, it is particularly advantageous compared to existing immunotherapies. Therefore, this specification The drug delivery compositions and devices described herein are related to the systemic administration of classical immunotherapy. To avoid potential toxicity, a vehicle for drug delivery at the site of tumor resection is needed. We provide this by concentrating immunotherapy agents at the site of tumor resection, thereby improving efficacy. In one embodiment, the drug delivery composition and device can delay tumor growth. To prevent and / or inhibit cancer recurrence, to prevent tumor metastasis, and It is useful for / to prevent the regrowth of the primary tumor.

[0072] In particular, in some embodiments, the present disclosure itself provides further immunosuppression (e.g., M This technology provides techniques for suppressing immune responses by promoting DSC activity.

[0073] While we do not wish to be bound by any particular theory, this disclosure is based on several states. In this regard, the techniques provided herein are generally observed in relation to chronic inflammation. (For example, often associated with autoimmune diseases), as described herein, The ability to mitigate the types of inflammation that can be activated in an acute setting (i.e., post-surgery) Describe what can be done. This disclosure targets p38 as described herein. This provides insight that the treatment may have unique utility in the context of tumor resection. For example, page 38 is described in relation to a specific autoimmune condition, and the treatment of such a condition is It has been targeted in the treatment of autoimmune diseases. Those skilled in the art have designed to treat autoimmune diseases. And / or many useful treatment strategies are those that worsen the phenotype of tumor progression. Given the consequences, it is understandable that setting up the tumor resection would be disastrous. This disclosure, despite this general principle, is not described herein. This demonstrates that targeting p38 is remarkably useful in cancer treatment. .

[0074] In some embodiments described, therapies targeting p38 are, for example, naturally Immune system activation / receptor activation (e.g., STING agonists or TLR agonists) It may be combined with other immunomodulatory strategies, such as those involving the administration of drugs.

[0075] Drug delivery compositions and devices Biomaterials (e.g., hydrogels) The drug delivery composition and device include a biomaterial. In one embodiment, the biomaterial is A scaffold or depot. A scaffold or depot is a drug as described herein. A delivery composition and device comprising any therapeutic agent, with sustained or long-term release thereof. It includes any synthetic or naturally occurring material suitable for promoting [the process]. Therefore, Biomaterials possess the advantageous properties of the compositions and devices described herein (for example, It possesses properties that provide storage modulus, biodegradability, and therapeutic agent release profile.

[0076] In one embodiment, the biomaterial facilitates the release of the therapeutic agent at the tumor resection site, and the same therapeutic agent... The duration is prolonged compared to administration in solution. In one embodiment, the biomaterial is administered to the tumor resection site. Compared to administration of the same therapeutic agent in a solution, the release of the therapeutic agent was measured for at least 5 minutes, then 10 minutes. Intervals: 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 Extend it for 5 days, 6 days, 7 days, 2 weeks, 3 weeks, or 4 weeks.

[0077] In some embodiments, when a biomaterial is evaluated at a specific point in time after administration, More of the therapeutic agent is present at the tumor resection site than when the agent is administered in solution. This extends the release of therapeutic agents (e.g., p38 MAPK inhibitors). For example, in some embodiments, When evaluated 24 hours after administration, it is released to the tumor resection site and present there. The amount of the therapeutic agent is at least greater than what would be observed if the therapeutic agent were administered in solution. 30% more (for example, at least 40%, at least 50%, at least 60%, at least 70%) (including at least 80%, at least 90%, or more). In some aspects If evaluated 48 hours after administration, it is released to the tumor resection site and present there. The amount of the therapeutic agent used is less than what would be observed if the therapeutic agent were administered in solution. Also 30% more (for example, at least 40%, at least 50%, at least 60%, at least 70%) (including %, at least 80%, at least 90%, or more). In some aspects In the case where the evaluation is performed 3 days after administration, it is released to the tumor resection site and present there. The amount of the therapeutic agent used is less than what would be observed if the therapeutic agent were administered in solution. Also 30% more (for example, at least 40%, at least 50%, at least 60%, at least 70%) (including %, at least 80%, at least 90%, or more). In some aspects In the case where the evaluation is performed 5 days after administration, it is released to the tumor resection site and present there. The amount of the therapeutic agent used is less than what would be observed if the therapeutic agent were administered in solution. Also 30% more (for example, at least 40%, at least 50%, at least 60%, at least 70%) (Containing %, at least 80%, at least 90%, or more).

[0078] In some aspects, the biomaterial is at least 500 Pa, at least 1000 Pa, and less All 1500 Pa, at least 2000 Pa, at least 2500 Pa, at least 3000 Pa, at least 4000 Pa, at least 5000 Pa, at least 10 kPa, at least 15 kPa, or higher stockpiled ammunition They are characterized by their sex rate. In some embodiments, biomaterials are characterized by having a sex rate of 50 kPa or less, or 40 kPa or less. Lower, 30kPa or less, 20kPa or less, 10kPa or less, 5000kPa or less, 4000Pa or less, 3000Pa or less, 2000Pa Characterized by the following, or lower, storage moduli: combinations of the above ranges. It is also possible. For example, in some aspects, biomaterials can be subjected to 500 Pa to 50,000 Pa. Or 1000 Pa to 20 kPa, or 1000 Pa to 10 kPa, or 1000 Pa to 5000 Pa, or 1000 Pa to 30 It is characterized by a storage modulus of 00 Pa.

[0079] In one embodiment, the biomaterial is hyaluronic acid, alginate, chitosan, chitin, sulfur Chondroitin acid, dextran, gelatin, collagen, starch, cellulose, polysaccharides , fibrin, ethylene vinyl acetate (EVA), poly(lactic acid-co-glycol) acid (PLGA), polymilk Acid (PLA), polyglycolic acid (PGA), polyethylene glycol (PEG), PEG diacrylate (P EGDA, disulfide-containing PEGDA (PEGSSDA), PEG dimethacrylate (PEGDMA), polydioxa Non(PDO), polyhydroxybutyrate (PHB), poly(2-hydroxyethyl methacrylate)(pHEMA) ), polycaprolactone (PCL), poly(beta-aminoester) (PBAE), poly(ester amine) Poly(propylene glycol) (PPG), poly(aspartic acid), poly(glutamic acid), Poly(propylene fumarate) (PPF), poly(sebacic anhydride) (PSA), poly(trimethylene carbonate) (PTMC), poly(desaminotyrosyltyrosine alkyl carbonate)(PDTE), poly[bis(t [Lifluoroethoxy)phosphazene], polyoxymethylene, single-walled carbon nanotube, Polyphosphazene, polyanhydrous, poly(N-vinyl-2-pyrrolidone) (PVP), poly(vinylal Poly(PVA), poly(acrylic acid) (PAA), poly(methacrylic acid) (PMA), polyacetal, Poly(alpha ester), poly(ortho ester), polyphosphoester, polyurethane, poly Recarbonate, polyamide, polyhydroxyalkanoate, polyglycerol, poly This includes glucuronic acid, its derivatives, and / or combinations thereof.

[0080] In one embodiment, the biomaterial is an uncrosslinked biomaterial or contains the same. In one aspect, the biomaterial is a cross-linked biomaterial or includes one. For example, in some embodiments, such crosslinked biomaterial is a hydrogel. , or including the same. The hydrogel is constructed using any method known in the art. It can be bridged. Those skilled in the art will know that in some cases, hydrogels can be, for example, chemical Effective cross-linking methods (for example, whether derived from natural sources or synthetic sources) By using a good small molecule crosslinking agent, polyvalent electrolyte crosslinking (for example, a certain polymer can be crosslinked in opposite directions) can be achieved. Mixing with a second polymer containing the charge, thermal induction crosslinking, photo-induced crosslinking (e.g., vinyl (Using sulfones, methacrylates, acrylic acids), pH-induced crosslinking, and / or enzyme catalysts You will understand that crosslinking can be done using crosslinking. In some embodiments, In forming hydrogels, Parhi, Adv Pharm Bull., Review 7(4): 515-530 One or more crosslinking methods described in (2017) can be used. In this context, hydrogels contain thiols (e.g., EXTRACEL®, HYSTEM®), Methacrylate, hexadecylamide (e.g., HYMOVIS®), and / or thyramine Crosslinking can be achieved by bonding MIN (for example, CORGEL®). In one embodiment, the hydrogel contains formaldehyde (e.g., HYLAN-A®). Divinyl sulfone (DVS) (e.g., HYLAN-B®), 1,4-butanediol diglycid Luether (BDDE) (e.g., RESTYLANE®), glutaraldehyde, and / or It can be directly crosslinked with genipin (for example, Khunmanee et al., "Crosslinking method of "Hyaluronic-based hydrogel for biomedical applications" J Tissue Eng. 8: 1-16(20 See 17). In some embodiments, the hydrogel is divinyl sulfone (DVS) (e.g. It is bridged by HYLAN-B(registered trademark).

[0081] In some aspects, the hydrogel biomaterial has at least 500 Pa and at least 100 0 Pa, at least 1500 Pa, at least 2000 Pa, at least 2500 Pa, at least 3000 Pa, small At least 4000 Pa, at least 5000 Pa, at least 10 kPa, at least 15 kPa, at least 20 kPa, at least 25kPa, at least 30kPa, at least 35kPa, at least 40kPa, or It is characterized by a higher storage modulus. In some embodiments, hydrogen The biomaterials are subject to pressures of 50kPa or less, 40kPa or less, 30kPa or less, 20kPa or less, 10kPa or less, and 5000Pa or less. Characterized by a storage modulus of 4000 Pa or less, 3000 Pa or less, 2000 Pa or less, or lower. It is possible. Combinations of the above ranges are also possible. For example, in some aspects Hydrogel biomaterials are typically subjected to pressures of 500 Pa to 50 kPa, or 1000 Pa to 50 kPa, or 1000 Pa to 20 kPa. or depending on the storage modulus of 1000 Pa to 10 kPa, or 500 Pa to 5000 Pa, or 500 Pa to 3000 Pa In some embodiments, the storage modulus of hydrogel biomaterials is This can be determined when it is completely saturated with an aqueous solution (e.g., water).

[0082] In some aspects, the biomaterial (e.g., hydrogel biomaterial) is at least 5 m Pa / s, at least 10 mPa / s, at least 20 mPa / s, at least 30 mPa / s, at least 40 mPa / s , at least 50 mPa / s, or a higher viscosity (e.g., 1000 s at 10°C) -1 At the shear rate Characterized by (more accurately measured). In some embodiments, hydrogel bio The materials are 50 mPa / s or less, 45 mPa / s or less, 40 mPa / s or less, 35 mPa / s or less, 30 mPa / s or less, and 25 mPa / s. Below, viscosity of 20 mPa / s, 15 mPa / s or less, 10 mPa / s or less, or lower (for example, at 10°C, 1000s -1 Characterized by (measured by the shear rate). The combination of the above ranges is also It is also possible. For example, in some aspects, hydrogel biomaterials can be subjected to 5-50 mPa Viscosity of 10-40 mPa / s, or 20-30 mPa / s (for example, 1000 s at 10°C) -1 shear rate Characterized by (measured by). In some embodiments, hydrogel The viscosity of a material can be measured using a rheometer.

[0083] In one aspect, a biomaterial (e.g., a hydrogel biomaterial) is hyaluronic acid, aluminum Ginate, Chitosan, Chondroitin Sulfate, Dextran, Gelatin, Collagen, Den Pun, cellulose, polysaccharide, fibrin, polyethylene glycol (PEG), PEG diacrylate PEG (PEGDA), disulfide-containing PEGDA (PEGSSDA), PEG dimethacrylate (PEGDMA), poly(2- Hydroxyethyl methacrylate (pHEMA), poly(beta-aminoester) (PBAE), poly( Aspartic acid, poly(glutamic acid), poly(propylene glycol) (PPG), poly(vinyl Polyalcohol (PVA), polyacetal, polyglycerol, polyglucuronic acid, or so It is a combination of these, or includes them. In one aspect, the biomaterial is hydro If it is a gel, the therapeutic agent of the composition or device is a hydrophilic molecule. In some embodiments, odor Therefore, if the biomaterial is a hydrogel, the therapeutic agent of the composition or device is a hydrophobic molecule. In one aspect, if the biomaterial is a hydrogel, then the composition or device The therapeutic agent is a hydrophobic or hydrophilic molecule. In one embodiment, the biomaterial is hydrogel If it is a device, the therapeutic agent of the composition or device is composed of hydrophobic and hydrophilic molecules.

[0084] In one embodiment, the biomaterial is hyaluronic acid or alginate. In this context, the biomaterial is cross-linked hyaluronic acid or cross-linked alginate. In one embodiment, the biomaterial comprises hyaluronic acid or alginate. The biomaterial contains cross-linked hyaluronic acid or cross-linked alginate. In some cases, the hydrogel is hyaluronic acid or alginate. Hydrogels are cross-linked hyaluronic acid or cross-linked alginate. In one embodiment, the hydrogel comprises hyaluronic acid or alginate. In this context, the hydrogel contains cross-linked hyaluronic acid or cross-linked alginate. .

[0085] In one embodiment, the biomaterial contains hyaluronic acid. In one embodiment, the biomaterial is , containing cross-linked hyaluronic acid. In one embodiment, the biomaterial is hyaluronic acid. In one embodiment, the biomaterial is cross-linked hyaluronic acid. In one embodiment, The hydrogel contains hyaluronic acid. In one embodiment, the hydrogel is crosslinked Contains hyaluronic acid. In one embodiment, the hydrogel is hyaluronic acid. In this context, the hydrogel is cross-linked hyaluronic acid.

[0086] Hyaluronic acid, also known as hyaluronan, is found throughout connective tissue, epithelial tissue, and nerve tissue. It is a widely distributed, anionic, non-sulfated glycosaminoglycan. The fact that it does not form in the Golgi, that it forms in the cell membrane instead of the Golgi, and that it can become very large, It is unique among glycosaminoglycans in that its molecular weight often reaches 1 million. ru.

[0087] Hyaluronic acid, one of the major components of the extracellular matrix, is essential for cell proliferation and Because it significantly contributes to migration, it plays an important role in cancer metastasis. In this context, hyaluronic acid levels correlate with malignancy and poor prognosis. Hyaluronic acid is, It is often used as a tumor marker for certain cancers (e.g., prostate cancer and breast cancer). It can also be used to monitor the progression of the disease in an individual. Therefore, hyaluronic acid as a biomaterial in the disclosed drug delivery composition and device The use of chlorophobic acid provides an unexpectedly useful and effective cancer treatment.

[0088] In one embodiment, hyaluronic acid is thiol (e.g., EXTRACEL®, HYSTEM( (Registered trademark), methacrylate, hexadecylamide (e.g., HYMOVIS®), and By attaching tyramine (for example, CORGEL®), crosslinking is possible. Hyaluronic acid also contains formaldehyde (e.g., HYLAN-A®), divinyl sulfide. Hon (DVS) (e.g., HYLAN-B(registered trademark)), 1,4-butanediol diglycidyl ether (BDD E) By (e.g., RESTYLANE®), glutaraldehyde, or genipin, directly It can be used to bridge bridges (for example, Khunmanee et al., "Crosslinking method of hyaluroni See "c-based hydrogel for biomedical applications" J Tissue Eng. 8: 1-16 (2017). In some embodiments, hyaluronic acid is mixed with divinyl sulfone (DVS) (e.g., HYLAN-B). Bridged by (registered trademark)

[0089] In one embodiment, hyaluronic acid is thiol-modified hyaluronic acid and a crosslinking agent. Includes. In one embodiment, the hydrogel is thiol-modified hyaluronic acid (e.g., G LYCOSIL (registered trademark), and thiol-reactive PEGDA crosslinking agents (e.g., EXTRALINK (registered trademark)). )) contains. In one embodiment, thiol-modified hyaluronic acid and thiol-reactive PEGD A crosslinking agent is used in combination with the drug delivery compositions and debacles described herein. It forms a cross-linked hydrogel that is useful in chairs.

[0090] In one embodiment, thiol-modified hyaluronic acid, thiol-reactive hyaluronic acid The amount and concentration of the crosslinking agent are determined based on the desired physical properties (storage ammunition of approximately 500 Pa to approximately 3000 Pa). To provide drug delivery compositions and devices having (such as) a high efficacy rate, It is possible.

[0091] In one embodiment, the biomaterial includes alginate. In one embodiment, the biomaterial is , containing cross-linked alginate. In one embodiment, the biomaterial is alginate. In one embodiment, the biomaterial is a cross-linked alginate. In one embodiment, The hydrogel contains alginate. In one embodiment, the hydrogel is crosslinked It contains alginate. In one embodiment, the hydrogel is alginate. In one embodiment, the hydrogel is a cross-linked alginate. The material does not contain alginate. In one aspect, the biomaterial is not alginate. In some aspects, hydrogels are not alginates. In some aspects, Idrogel does not contain alginate.

[0092] In one embodiment, the alginate is to which a crosslinking salt (e.g., calcium chloride) is added. This allows for ionic crosslinking.

[0093] In one embodiment, the alginate is an alginate and a crosslinking agent (e.g., calcium chloride) It contains (m). In one embodiment, the hydrogel contains alginate and a crosslinking agent (e.g., chloride). Contains calcium. In one embodiment, alginate and calcium chloride (e.g., io The crosslinking agent is combined with the drug delivery compositions and drugs described herein. It forms a cross-linked hydrogel that is useful in vise applications.

[0094] In one embodiment, the amounts and concentrations of alginate and calcium chloride are desired. Drug delivery compositions having physical properties (such as having a storage modulus of approximately 500 Pa to approximately 3000 Pa) It can be adjusted to provide goods and devices.

[0095] In one aspect, the biomaterial is a hydrophobic polymer. The rimer is made from ethylene vinyl acetate (EVA), poly(lactic acid-coglycol) acid (PLGA), and polylactic acid (P LA), polyglycolic acid (PGA), polydioxanone (PDO), polyhydroxybutyrate (PHB), poly Caprolactone (PCL), poly(esteramide), poly(propylene fumarate) (PPF), poly( (Sebacic anhydride) (PSA), poly(trimethylene carbonate) (PTMC), poly(desaminotyrosyltyro) Synalkyl carbonate (PDTE), poly[bis(trifluoroethoxy)phosphazene], Polyoxymethylene, single-walled carbon nanotubes, polyphosphazenes, polyanhydrides, poly (N-vinyl-2-pyrrolidone) (PVP), poly(acrylic acid) (PAA), poly(methacrylic acid) (PMA), Poly(alpha ester), poly(ortho ester), polyphosphoester, polyurethane, poly These are recarbonates, polyamides, or polyhydroxyalkanoates. Hydrophobic poly The use of Mar as a biomaterial is possible when the therapeutic agent in the composition or device is hydrophilic. It may be particularly useful. Hydrophobic therapeutic agents contribute by imparting therapeutic effects through their release properties. Release over a longer period (e.g., several days / weeks) rather than on a short scale (e.g., several hours). It is expected that this will be done. Therefore, in one aspect, biomaterials are hydrophobic If it is a rimer, the therapeutic agent of the composition or device is a hydrophilic molecule.

[0096] In one embodiment, the biomaterial includes a cross-linked biopharmaceutical. In one embodiment, Io formulations use dithio-bis(ethyl 1H-imidazo) as a self-immolating crosslinking agent. It is crosslinked by (DIC)(1-carboxylate). In one embodiment, the result is The hydrogel is loaded with small molecules.

[0097] Inhibitors of pro-inflammatory pathways The drug delivery composition and device may contain an inhibitor of the pro-inflammatory pathway. The product and device may contain inhibitors of one or more pro-inflammatory pathways. In this manner, inhibitors of pro-inflammatory pathways may prevent the recruitment of immunosuppressive cells. In some embodiments, inhibitors of pro-inflammatory pathways may prevent acute inflammation. In this context, inhibitors of pro-inflammatory pathways, for example, one or more pro-inflammatory sites Production of ions (e.g., TNF-alpha, IL-1β, and / or IL-6), increased Th1 cell activity It may inhibit inflammatory immune responses, including the mobilization of myeloid cells, including cell proliferation and / or proliferation. For example, in some embodiments, an inhibitor of the pro-inflammatory pathway is an inhibitor of IL-1β. Good. In some embodiments, the inhibitor of the pro-inflammatory pathway may be an IL-6 inhibitor.

[0098] In one embodiment, an inhibitor of the pro-inflammatory pathway is p38 as described herein. Pro-inflammatory immune response mediated by the mitogen-activated protein kinase (MAPK) pathway It is an inhibitor of [the disease].

[0099] In one aspect, inhibitors of pro-inflammatory pathways prevent the recruitment of immunosuppressive cells. In this embodiment, the inhibitor of the pro-inflammatory pathway is CCR2, CCR5, CXCR2, CXCR4, CXCL12, or CC It is an L2 inhibitor, antagonist, or partial agonist. In one embodiment, it induces inflammation. Inhibitors of the pathway include inhibitors, antagonists, or partial inhibitors of CCR5, CXCR2, CXCL12, or CCL2. He is an agonist.

[0100] In one aspect, inhibitors of pro-inflammatory pathways include CCR2 inhibitors, antagonists, or partial inhibitors. It is a segmental agonist. In one embodiment, CCR2 is associated with the p38 MAPK pathway (e.g., Mon Tague et al., J. Inflammation 2018, 15:101; and Xu et al., Am. J. Transl. Res. (As described in 2017, 9, 2878-2890). In one embodiment, an inhibitor of CCR2, The agonist or partial agonist is PF-04136309, CCX872-B, or prozarizumab (pl (ozalizumab). In one embodiment, the inhibitor of the pro-inflammatory pathway is PF-04136309, CCX872 -B or prozarizumab. In one embodiment, an inhibitor of the pro-inflammatory pathway inhibits CCR2. It is not a harmful agent, antagonist, or partial agonist. In one aspect, it is an anti-inflammatory pathway. The inhibitor is not PF-04136309.

[0101] In one aspect, inhibitors of the pro-inflammatory pathway include CCR5 inhibitors, antagonists, or part It is a segmental agonist. In one embodiment, CCR5 is associated with the p38 MAPK pathway (e.g., Lei , et al., Biochem. Biophys. Res. Commun. 2005, 329, 610-615; and Manes, et al. (As described in J. Exp. Med. 2003, 198, 1381-1389). In one aspect, CCR5 inhibitors, antagonists, or partial agonists include maraviroc, DAPTA, and GSK706769. These are INCB009471, GW873140, Bicribiroc or PRO 140. In one embodiment, inflammation Inhibitors of the induction pathway include maraviroc, DAPTA, GSK706769, INCB009471, GW873140, and bicribi. It is either Roku or PRO 140.

[0102] In one aspect, inhibitors of pro-inflammatory pathways include inhibitors of CCR2 and CCR5, and antagonists. It is a CCR2 and CCR5 inhibitor, an antagonist. In one embodiment, it is a CCR2 and CCR5 inhibitor, an antagonist. The agonist or partial agonist is PF-04634817, Seniclivilok, or BMS-813160. In one embodiment, inhibitors of the pro-inflammatory pathway include PF-04634817, senicliviroc, and This is BMS-813160.

[0103] In one aspect, inhibitors of pro-inflammatory pathways include CXCR2 inhibitors, antagonists, or It is a partial agonist. In one embodiment, it is a CXCR2 inhibitor, antagonist or partial The agonist is Danilixin, QBM076, SX-682, or SB225002. In one embodiment Inhibitors of the pro-inflammatory pathway include Danilixin, QBM076, SX-682, or SB225002.

[0104] In one embodiment, inhibitors of pro-inflammatory pathways include CXCR4 inhibitors, antagonists, or It is a partial agonist. In one embodiment, CXCR4 is associated with the p38 MAPK pathway (e.g., Lei, et al., Biochem. Biophys. Res. Commun. 2005, 329, 610-615; and Trushin, e. (As described in t al., J. Immunol. 2007, 178, 4846-4853). In a certain manner Therefore, CXCR4 inhibitors, antagonists, or partial agonists include prelixafor, AMD070. , AMD3465, AMD11070, LY2510924, MSX-122, TG-0054, CX-01, X4P-001, BL-8040, USL31 It is 1 or SP01A. In one embodiment, the inhibitor of the pro-inflammatory pathway is plerixafor, AM D070, AMD3465, AMD11070, LY2510924, MSX-122, TG-0054, CX-01, X4P-001, BL-8040, U It is SL311 or SP01A. In one embodiment, the inhibitor of the pro-inflammatory pathway is an inhibitor of CXCR4. They are neither antagonists nor sub-agonists.

[0105] In one embodiment, inhibitors of pro-inflammatory pathways include CXCL12 inhibitors, antagonists, or It is a partial agonist. In one embodiment, CXCL12 is associated with the p38 MAPK pathway (e.g., This is described in Gao, et al., Int. J. Clin. Exp. Pathol. 2018, 11, 3119-3125. (As is).

[0106] In one embodiment, an inhibitor of the pro-inflammatory pathway is a CCL2 inhibitor, antagonist, or part It is a segmental agonist. In one embodiment, CCL2 is associated with the p38 MAPK pathway (e.g., Cho , et al., J. Neuroimmunol. 2008, 199, 94-103; and Marra, et al., Am. J. Physio (As described in l. Gastrointest. Liver Physiol. 2004, 287, G18-26). In this embodiment, CCL2 inhibitors, antagonists, or partial agonists are vindalit (b (indarit)

[0107] In one embodiment, inhibitors of pro-inflammatory pathways include PF-04136309, CCX872-B, and prozarizma. Bu, Maraviroc, DAPTA, GSK706769, INCB009471, GW873140, Bikuribirok, PRO 140, P F-04634817, Senicliviroc, BMS-813160, Danilixin, QBM076, SX-682, SB225002, Prelixafor, AMD070, AMD3465, AMD11070, LY2510924, MSX-122, TG-0054, CX-01, X These are 4P-001, BL-8040, USL311, or SP01A.

[0108] In one aspect, inhibitors of pro-inflammatory pathways include CCX872-B, prozarizumab, and maraviroc. DAPTA, GSK706769, INCB009471, GW873140, Bikuribiroku, PRO 140, PF-04634817, Se Nicliviroc, BMS-813160, Danilixin, QBM076, SX-682, SB225002, Prelixafor , AMD070, AMD3465, AMD11070, LY2510924, MSX-122, TG-0054, CX-01, X4P-001, BL-804 0, USL311, or SP01A.

[0109] In one aspect, inhibitors of pro-inflammatory pathways prevent acute inflammation. Inhibitors of the pro-inflammatory pathway include anti-IL-1α antibodies, anti-IL-1β antibodies, anti-IL-1R antibodies, IL-1 inhibitors, and anti-IL-1 inhibitors. L-6 antibody, anti-IL-6R antibody, anti-IL17 antibody, anti-IL-17A antibody, anti-IL-17RA antibody, anti-IL-23 / IL-12 antibody , or an anti-IL-23 antibody.

[0110] In one embodiment, the inhibitor of the pro-inflammatory pathway is an anti-IL-1α antibody. The anti-IL-1α antibody is MABp1. In one embodiment, the inhibitor of the pro-inflammatory pathway is MABp1. be.

[0111] In one embodiment, the inhibitor of the pro-inflammatory pathway is an anti-IL-1β antibody. IL-1β is associated with the p38 MAPK pathway (e.g., Kulawik, et al., J. Biol. Chem. 2017). 292, 6291-6302;Rovin, et al., Cytokine 1999, 11, 118-126;Laporte, et al., Am. J. Physiol. Lung Cell Mol. Physiol. 2000, 279, L932-L941;Baldassare, et al., J Immunol. 1999, 162, 5367-5373; and Weber, et al. Sci. Signal. 2010, 3, cm1. (As described in [location]). In one embodiment, the anti-IL-1β antibody is canakinumab. In one embodiment, the inhibitor of the pro-inflammatory pathway is canakinumab.

[0112] In one embodiment, the inhibitor of the pro-inflammatory pathway is an anti-IL-1R antibody. IL-1R is associated with the p38 MAPK pathway (e.g., Weber, et al., Sci. Signal. 2010, 3, c (As described in m1; and Jain, et al., Nat. Commun. 2018, 9:3185). In a certain manner Therefore, anti-IL-1R antibodies are anakinra. In one embodiment, inhibitors of pro-inflammatory pathways are It's Anakinra.

[0113] In one embodiment, the inhibitor of the pro-inflammatory pathway is an IL-1 inhibitor. In one embodiment, The IL-1 inhibitor is lilonacept. In one embodiment, the inhibitor of the pro-inflammatory pathway is lilonacept. It is a nacept.

[0114] In one embodiment, the inhibitor of the pro-inflammatory pathway is an anti-IL-6 antibody. In another embodiment, IL-6 is associated with the p38 MAPK pathway (e.g., Sinfield, et al., Biochem. Biophys. Res.). Commun. 2013, 430, 419-424; Suzuki, et al., FEBS Lett. 2000, 465, 23-27; and N As described in Ishikai-Yan Shen, et al., PLoS One 2017, 12, 1-17. In this embodiment, the anti-IL-6 antibody is olokizumab, crazakizumab, OPR-003, silkumab, A These are RGX-109, FE301, or FM101. In one embodiment, the inhibitor of the pro-inflammatory pathway is Oro These are kizumab, crazakizumab, OPR-003, silkumab, ARGX-109, FE301, or FM101. .

[0115] In one embodiment, the inhibitor of the pro-inflammatory pathway is an anti-IL-6R antibody. The anti-IL-6R antibody is tocilizumab, sarilumab, or bovalilizumab. In some embodiments In this context, the inhibitors of the pro-inflammatory pathway are tocilizumab, sarilumab, or bovalilizumab. ru.

[0116] In one embodiment, the inhibitor of the pro-inflammatory pathway is an anti-IL-17 antibody. IL-17 is associated with the p38 MAPK pathway (e.g., Noubade, et al., Blood 2011, 118, 3290). -3300;Roussel, et al., J. Immunol. 2010, 184, 4531-4537; and Mai, et al., J. (As described in Biol. Chem. 2016, 291, 4939-4954). In one embodiment, anti-I L-17 antibodies include ixekizumab, bimekizumab, ALX-0761, CJM112, and CNTO 67. These are 85, LY3074828, SCH-900117, or MSB0010841. In one embodiment, the pro-inflammatory pathway The inhibitors are ixekizumab, bimekizumab, ALX-0761, CJM112, CNTO 6785, and LY3074828. These are SCH-900117 or MSB0010841.

[0117] In one embodiment, the inhibitor of the pro-inflammatory pathway is an anti-IL-17A antibody. The anti-IL17A antibody is secukinumab. In one embodiment, an inhibitor of the pro-inflammatory pathway is It is secukinumab.

[0118] In one embodiment, the inhibitor of the pro-inflammatory pathway is an anti-IL-17RA antibody. The anti-IL17RA antibody is brodalumab. In one embodiment, an inhibitor of the pro-inflammatory pathway is It is brodalumab.

[0119] In one embodiment, the inhibitor of the pro-inflammatory pathway is an anti-IL-23 / IL-12 antibody. In this context, the anti-IL-23 / IL-12 antibody is ustekinumab or briakinumab. In this context, inhibitors of the pro-inflammatory pathway are ustekinumab or briakinumab.

[0120] In one embodiment, the inhibitor of the pro-inflammatory pathway is an anti-IL-23 antibody. IL-23 is associated with the p38 MAPK pathway (e.g., Tang, et al., Immunology 2012, 135, 11 2-124; and Canavese, et al., J. Clin. Exp. Dermatol. Res. 2011, S2:002. doi:10 (As described in .4172 / 2155-9554). In one embodiment, the anti-IL-23 antibody is CHILD. The inflammatory pathway is drakizumab, BI 655066, or guselkumab. In one embodiment, the pro-inflammatory pathway The inhibitors for this are tildrakizumab, BI 655066, or guselkumab.

[0121] In one embodiment, inhibitors of pro-inflammatory pathways include MABp1, canakinumab, anakinra, and ri. Lonacept, Orokizumab, Clazakizumab, OPR-003, Silkumab, ARGX-109, FE301, FM101, tocilizumab, sarilumab, bovalilizumab, ixekizumab, bimekizumab, A LX-0761, CJM112, CNTO 6785, LY3074828, SCH-900117, MSB0010841, Secukinumab, Bu Rhodalumab, ustekinumab, briakinumab, tildrakizumab, BI 655066 or Guse It is lucumab.

[0122] In one aspect, the inhibitor of the pro-inflammatory pathway is a TGFβR inhibitor. TGFβR is associated with the p38 MAPK pathway (e.g., Yu et al., EMBO J. 2002, 21, 3749-375). 9;Sato, et al., J. Invest. Dermatol. 2002, 118, 704-711; and Hanafusa, et al. (As described in J. Biol. Chem. 1999, 274, 27161-27167). In a certain manner Therefore, the TGFβR inhibitor is garnicertib. In one aspect, it is an inhibitor of the pro-inflammatory pathway. It is Garnicercib.

[0123] In one aspect, inhibitors of pro-inflammatory pathways act as inflammatory resolving mediators (specialized It is a pro-resolving mediator (SPM) or contains one. SPM is derived from long-chain fatty acids. Lipid mediators that prevent excessive inflammation and / or acute inflammatory responses It participates in a collaborative convergence program to bring the results to a convergence. An example of such an SPM is, for example, Araki Examples include lipoxins derived from duloc acid (AA) and resolvins derived from docosahexaenoic acid (DHA). The inflammation is resolved through specific cell surface receptors without compromising the host's defenses. It soothes, enhances efferocytosis, and transmits signals to repair tissue damage. It is an active process that involves the production of molecules. For example, Cai et al., "MerTK cleavage limits “proresolving mediator biosynthesis and worsens tissue inflammation” PNAS, 1 13: 6526-6531 (2016); and Serhan et al., "Novel anti-inflammatory - Pro-resolving See "Mediators and their receptors," Curr Top Med Chem 11: 629-647 (2011). The oxygenase enzyme (e.g., COX-2) may be involved in the production of certain SPMs.

[0124] In some embodiments, SPM, which may be useful as an inhibitor of pro-inflammatory pathways, is a resol It is either a resolvin or contains one. Resolvin acts on tumor cells via macrophage phagocytosis. Enhances cellular debris clearance, for example, TNFα, IL-6, IL-8, CCL4 and / or CCL5 It was shown to counterregulate the release of cytokines / chemokines. For example, Sulciner et al., "Resolvins suppress tumor growth and enhance cancer therapy" See "J Exp Med 215: 115-140(2018)". Resolvins (Rv) are classified into several classes: Resolvins Ds (RvDs) derived from docosahexaenoic acid (DHA); Resolvins Es (RvEs) derived from eicosapentaenoic acid (EPA); Resolvin D derived from DPA isomers, osbonic acid; Resolvin D (RvD ); Resolvin D n-6DPA (RvD n-6DPA ) derived from DPA isomers, culpanodonic acid; Resolvin Ts (RvTs) derived from culpanodonic acid (in contrast to RvD (having a 17S-hydroxyl residue), which has a 17R-hydroxyl residue n-3DPA (RvD n-3DPA ). Those skilled in the art will understand that in some cases, resolvins are RvD1, RvD2, RvD3, RvD4, RvD5 , RvD6, 17R-RvD1, 17R-RvD2, 17R-RvD3, 17R-RvD4, 17R-RvD5, 17R-RvD6, RvE1, 18S-Rv n-3DPA E1, RvE2, RvE3, RvT1, RvT2, RvT3, RvT4, RvD1 , RvD2 , RvD5 , or combinations thereof or include them. n-3 n-3 n-3

[0125] In some embodiments, SPMs that may be useful as inhibitors of inflammatory pathways are lipoxins (e.g., including LxA4, LxB4, 15-epi-LxA4, and / or 15-epi-LxB4), protectins / neuroprotectins (e.g., protectins / neuroprotectins derived from DHA and / or protectins / neuroprotectins derived from n-3 DPA), maresins (e.g., derived from DHA ), and / or protectins / neuroprotectins derived from n-3 DPA), maresins (e.g., derived from DHA Malecin derived from other DPAs and / or n-3 DPAs, as well as other DPA metabolites, Or this includes.

[0126] Pro-inflammatory immunity mediated by the P38 mitogen-activated protein kinase (MAPK) pathway Inhibitors of response This disclosure particularly relates to p38 mitogen activity at target sites (e.g., tumor resection sites). Inhibiting the pro-inflammatory immune response mediated by the protein kinase (MAPK) pathway ( For example, p38 modulates (e.g., inhibits) the p38 MAPK-mediated pro-inflammatory pathway or its components. 8. Administration of MAPK inhibitors (see, for example, Figures 4-6) reduces the risk of cancer recurrence. Recognize that this can extend survival. MAPK-targeted therapy ( For example, inhibition of the BRAF / MEK / ERK module is an anti-PD-1 immune checkpoint blocker therapy. It induces a transcriptional signature associated with resistance, which in turn affects anti-PD-1 / L1 cancer therapy. It has been reported that this can have a negative impact on responsiveness (for example, Hugo et al., (See Cell 2016, 165, 35-44), inhibiting MAPK can promote antitumor immunity. That was unexpected.

[0127] Therefore, in some embodiments, what is provided herein is p38 mite Inhibition of pro-inflammatory immune responses mediated by the Gen-activated protein kinase (MAPK) pathway. This invention relates to drug delivery compositions and devices containing a drug. In some embodiments, the following is described herein: The drug delivery compositions and devices provided are one more than p38 mitogen activation Even if it includes inhibitors of pro-inflammatory immune responses mediated by the protein kinase (MAPK) pathway good.

[0128] The MAPK p38 family includes the p38α, p38β, p38γ, and p38δ isoforms. MAPK is activated by numerous immune receptors, thereby affecting both the upstream and downstream of p38. Inhibition of a signaling module or regulatory target that functions in any of these means that it mediates This may provide an effective and selective method for inhibiting molecular pathways and pro-inflammatory immune responses. .

[0129] For example, p38 MAPK is mitogen-activated protein kinase kinase 3 (MAP2K3), Itogen-activated protein kinase kinase 6 (MAP2K6), mitogen-activated protein Quality kinase kinase kinase 1 (MAP3K1), and / or mitogen-activated protein kinase It can be activated by naze kinase kinase 4 (MAP3K4). Therefore, it is upstream of p38 MAPK. Inhibiting the target of p38 MAPK may be effective in inhibiting the p38 MAPK pathway.

[0130] Inhibition of downstream targets of p38 MAPK may also be an effective means of inhibiting the p38 MAPK pathway. Downstream of p38 MAPK, for example, mitogen-activated protein kinase interacting protein kinase MNK1 (mitogen-activated protein kinase interacting protein kinase) 1 and 2 MNK kinases (and MNK2) are activated by the p38 MAPK pathway. MNK kinases regulate mRNA translation. It plays an important role in this process, and as a result, the progression of cancer, drug resistance, and pro-inflammatory reactions. It is an important mediator in the production of itokines and cytokine signaling. Togen- and stress-activated kinases 1 and 2 (M SK1 and MSK2 are also downstream targets of p38 MAPK and influence the inflammatory response. Kinase-activated protein kinases 2, 3, and 5 (MK2, MK3, MK5) are activated by p38 MAPK. It is transformed and involved in cellular stress and inflammatory responses.

[0131] Considering the above, inhibiting the p38 MAPK pathway could improve the therapeutic strategy for treating cancer. It can provide, in particular, local inflammatory wound responses and systemic inflammatory processes together. , activate dormant micrometastases or induce proliferation of residual cancer cells, thereby This may increase the risk of recurrence. Therefore, the p38 MAPK pathway at the tumor resection site By inhibiting the mediated pro-inflammatory immune response, it reduces the risk of cancer recurrence and... This could extend the lifespan of elephants.

[0132] In one embodiment, inhibitors of pro-inflammatory immune responses mediated by the p38 MAPK pathway are p3 8. MAP kinase inhibitors. In one embodiment, p38 MAP kinase inhibitors are p38α, p38 It is an inhibitor of β, p38γ, and / or p38δMAP kinase. In one embodiment, p38 MA P-kinase inhibitors include semapimod, pexmetinib, BMS-582949, and rosmapimod. Mod, pamapimod, larimetinib, dramapimod, VX-702, VX-745, TAK-715 , SB239063, SB202190, SB203580, SCIO 469, PH-797804, AZD7624, ARRY-797, ARRY-614 AVE-9940, LY3007113, Skepinon-L, UM-164, SCIO 323, SX-011, SK-F860002, SB706 504, SB681323, CHF-6297, RWJ-67657, Org48762-0, ML3403, JX-401, EO-1428, DBM 128 5, AMG-548, AL-8697, PD-169316, PF-03715455, PH-797804, Celone Cellulite, Solafene It is either nib or dilmapimod. In one embodiment, it is a p38 MAP kinase inhibitor. The agents are quinazolinone, pyrimidopyrimidone, pyridopyrimidone, pyrazole, and quinolinone. It comprises a n and / or naphthilidinone core structure. In one embodiment, it inhibits p38 MAP kinase The harmful agent is rosmapimod.

[0133] In one embodiment, inhibitors of pro-inflammatory immune responses mediated by the p38 MAPK pathway are p3 It is an inhibitor of 8α, p38β, p38γ, and / or p38δ MAP kinase. In one embodiment Inhibitors of pro-inflammatory immune responses mediated by the p38 MAPK pathway include semapimod and pexme. Tinib, BMS-582949, Rosmapimod, Pamapimod, Larimetinib, Dramapimod, VX-702 , VX-745, TAK-715, SB239063, SB202190, SB203580, SCIO 469, PH-797804, AZD7624, A RRY-797, ARRY-614, AVE-9940, LY3007113, Skepinon-L, UM-164, SCIO 323, SX-011, SK-F860002, SB706504, SB681323, CHF-6297, RWJ-67657, Org48762-0, ML3403, JX-401 , EO-1428, DBM 1285, AMG-548, AL-8697, PD-169316, PF-03715455, PH-797804, Theron These are celtib, sorafenib, or dilmapimod. In one embodiment, the p38 MAPK pathway Inhibitors of more mediated pro-inflammatory immune responses include quinazolinone, pyrimidopyrimidone, Includes pyridopyrimidone, pyrazole, quinolinone, and / or naphthilidinone core structures In one embodiment, an inhibitor of the pro-inflammatory immune response mediated by the p38 MAPK pathway is It is rosmapimod.

[0134] In one embodiment, a p38 MAP kinase inhibitor is at least one p38 MAP kinase, e.g. For example, it binds to the ATP binding site of p38α, p38β, p38γ and / or p38δ MAP kinases. In one embodiment, a p38 MAP kinase inhibitor is at least one p38 MAP kinase, e.g. For example, allosteric inhibitors of p38α, p38β, p38γ and / or p38δ MAP kinases. ru.

[0135] In one embodiment, inhibitors of pro-inflammatory immune responses mediated by the p38 MAPK pathway are p3 8 is an inhibitor of upstream effects of MAPK. In one embodiment, the p38 MAPK pathway is a medium Inhibitors of the mediated pro-inflammatory immune response include RIPK1, RIPK2, RIPK3, RIPK4, RAC1, CDC42, M TK1, TAK1, MEKK1, MEKK2, MEKK3, MEKK4, DLK, MLK2, TAO1, TAO2, TLP2, TPL2, ASK1, It is an inhibitor of MKK3, MKK4 and / or MKK6. In one embodiment, via the p38 MAPK pathway Inhibitors of mediated pro-inflammatory immune responses are inhibitors of downstream effectors of p38 MAPK. In one embodiment, inhibitors of pro-inflammatory immune responses mediated by the p38 MAPK pathway are Inhibitors of MK2, MK3, MNK1, MNK2, MSK1, MSK2, MSK3, RSK, PP2A and / or cPLA2 ru.

[0136] In some embodiments, those skilled in the art will know that pro-inflammatory immune responses mediated by the p38 MAPK pathway The inhibitors of the answer (e.g., p38 MAPK inhibitors) are cyclooxygenase (COX)-1 and / or COX- It is important to understand that the activity and / or expression of 2 can be regulated (e.g., inhibited). It is possible. For example, Matsui et al., "Release of prostaglandin E2 and nitric oxide from sp inal microglia is dependent on activation of p38 mitogen-activated protein kinas See "e" Anesthesia & Analgesia, 111(2): 554-560 (2010).

[0137] In some embodiments, those skilled in the art will know of certain COX inhibitors (e.g., COX-1 and / or CO X-2 inhibitors) and / or other anti-inflammatory drugs (e.g., nonsteroidal anti-inflammatory drugs (NSAIDs) and / Or anti-inflammatory analgesics) are modifiers (e.g., inhibitors) of the p38 MAPK pathway or its components. They will understand that it can act as such (for example, Esposito et al., "Non-ste "Roidal anti-inflammatory drugs in Parkinson's disease" Experimental Neurology 2 05: 295-312 (2007); Desai et al., “Mechanisms of Phytonutrient Modulation of Cycloox ygenase-2 (COX-2) and Inflammation Related to Cancer” Nutrition and Cancer, 70: 350-375 (2018); Huang et al., “MAPK / ERK signal pathway involved expression of COX-2 and VEGF by IL-1beta induced in human endometriosis stomal cells in vitro” Int J Clin Exp Pathol, 6: 2129-2136 (2013); and Di Mari et al., “HETEs enhance IL-1-med iated COX-2 expression via augmentation of message stability in human colonic my Am J Physiol-Gastrointest Liver Physiol., 293: 2092-2101 (2007) (See the description provided below). Therefore, in some aspects, COX-2 inhibitors and Other anti-inflammatory agents include p38 MAPK inhibitors as described herein (and (and / or may be used as such); or, in addition, in several manner In addition, such COX inhibitors or other anti-inflammatory agents are other p as described herein. 38. May be used in combination with MAPK inhibitors.

[0138] In some embodiments, COX inhibitors are non-selective COX-1 and / or COX-2 inhibitors. It may exist. In some embodiments, COX inhibitors selectively target COX-1 and / or COX -2 inhibitors may also be used.

[0139] In some embodiments, p38 MAPK pathway inhibitors (i.e., p38 MAPK pathway or its structure) As a specific COX inhibitor useful as an inhibitor of the active ingredient, but not limited to this, non-stereo Non-steroidal anti-inflammatory drugs (NSAIDs) are examples. In some embodiments, NSAIDs are, for example, typical Specifically, cyclooxygenase (COX-1) is involved in the production of prostaglandins involved in inflammation. Inflammation can be reduced by inhibiting the activity of the enzyme (and / or COX-2).

[0140] In some embodiments, NSAIDs for use as p38 MAPK pathway inhibitors are typical This includes celecoxib, known as a selective COX-2 inhibitor, or a combination thereof. Chen et al., “Celexocib inhibits the lytic activation of Kaposi's sarcoma-assoc iated herpesvirus through down-regulation of RTA expression by inhibiting the ac "Tivation of p38 MAPK" Viruses 7:2268-2287 (2015); and Fan et al., "Celecoxib atten uates systemic lipopolysaccharide-induced brain inflammation and white matter in See "Jury in the neonatal rats," Neuroscience 240: 27-38 (2013).

[0141] In some embodiments, NSAIDs for use as p38 MAPK pathway inhibitors are used in ketologic It is or contains ketolac. Ketolac is obtained, for example, by competitive blockade of the COX enzyme. It is known to inhibit prostaglandin synthesis. In some embodiments, keto Lolac can reduce IL-6 expression. For example, Singh et al., "A prospective s tudy to assess the levels of interleukin-6 following administration of diclofena c, ketorolac and tramadol after surgical removal of lower third molars” J. Maxil See lofac Oral Surg. 14: 219-225 (2015). Those skilled in the art will also know that ketrolak is known to inhibit It should be understood that it can act as a non-selective COX inhibitor with inflammatory properties. However, I do not wish to be constrained by any particular theory, but in some aspects, ketrolak It is thought that it may have higher selectivity in inhibiting COX-1 than COX-2. (See Hersh and Dionne, "Nonopioid analgesics" (Pharmacology and Therapeutics f) (See Dentisty (7th edition), Dowd et al., Elsevier Inc. 2017). Ketrolac is used for short-term pain relief. It has traditionally been used for pain management, and therefore typically lasts longer than 5 days. Not prescribed for use in this disclosure. In some embodiments, ketro Rak is a condition in which immunosuppressive inflammation induced by tumor resection surgery is inhibited or reduced. So that it can be done, for at least 5 days or longer, for example, at least 6 days, at 7 days, at least 8 days, at least 9 days, at least 10 days, or longer During this time, it is released from the biomaterial (for example, as described herein). Trolac can be administered as a racemic mixture or as individual enantiomers, e.g., S- It may be administered as an enantiomer.

[0142] Other examples of NSAIDs useful in accordance with this disclosure, but not limited to these, include: Examples include: (i) salicylates (e.g., acetylsalicylic acid, diflunisal, salicylic acid) (ii) Acids and other salicylates and / or salsalates); (ii) Propionic acid derivatives (e.g.) For example, ibuprofen, dexibprofen, naproxen, fenoprofen, ketop Lofen, dexketoprofen, flurbiprofen, oxaprozin, and / or (iii) Loxoprofen; (iii) Acetate derivatives (e.g., indomethacin, tolmetin, sulinda) C, etodolac, ketrolac, diclofenac, aceclofenac, and / or nab (iv) Enolic acid (oxicam) derivatives (e.g., piroxicam, meton); (iv) Enolic acid (oxicam) derivatives (e.g., piroxicam, meton) Roxicam, Tenoxicam, Doroxicam, Loroxicam, Isoxicam, and / or (v) anthranilic acid derivatives or fenamic acid (e.g., mefena) (vi) Selective COX-2 inhibitors (e.g., celecoxib, rofecoxib, valdecoxib, parecoxib) Lumiracoxib, etoricoxib, and / or firocoxib; (vii) sulfonated anions (e.g., nimeslide); (viii) Others (e.g., clonyxin, lycopherone [e.g., [Acts by inhibiting lipoxygenase (LOX) and COX], and / or H-H Rupazide, and combinations thereof.

[0143] As will be understood by those skilled in the art, in some embodiments, for example, as shown in Figure 5 Bikkavilli et al. have shown that "p38 mitogen-activated protein kinase regulates canonic al Wnt-β-catenin signaling by inactivation of GSK3β” Journal of Cell Science, As described in 121: 3598-3607 (2008), p38 MAPK inhibitors are Wnt-β-catenin It is possible to regulate (e.g., inhibit) the pathway or its components. Therefore, how many In that embodiment, an inhibitor of the pro-inflammatory immune response mediated by the p38 MAPK pathway is Wnt In some embodiments, the p38 MAPK pathway may be included. Inhibitors of pro-inflammatory immune responses mediated by this include GSK3β inhibitors, or this It may also include: In some embodiments, pro-inflammatory immunity mediated by the p38 MAPK pathway. The inhibitor of the epidemic response may be a β-catenin inhibitor, or may include one.

[0144] Those skilled in the art will also know that certain Wnt / β-catenin pathway inhibitors may affect the p38 MAPK pathway or its components. It will be understood that it can act as a modifying factor (e.g., an inhibitor) (e.g., Andre et al.) , “Wnt5a and Wnt11 regulate mammalian anterior-posterior axis elongation”Devel Opment 142: 1516-1527 (2015); and Ma et al., "Crosstalk between Wnt / β-catenin and NF-κB signaling pathway during inflammation” Front Immunol. 7: 378 (2016). (See the description below). Therefore, in some aspects, the Wnt / β-catenin pathway Pathway inhibitors may be p38 MAPK inhibitors as described herein (and / also (This may be used as such; or, in addition, in some embodiments, Such Wnt / β-catenin pathway inhibitors are other p38 MAPKs as described herein. It may be used in combination with an inhibitor.

[0145] Activators of the innate immune response The drug delivery composition and device may contain an activator of the innate immune response. The composition and device may contain one or more activators of the innate immune response. The main function of the innate immune response is the involvement of specialized chemical mediators (e.g., cytokines). Recruiting immune cells to the site of infection through the production of biochemical factors; identifying bacteria and activating cells Activating the complement cascade, which promotes the clearance of antibody complexes or dead cells. Sexualization; the removal of foreign substances present in organs, tissues, blood, and lymph by specialized white blood cells. Identification and removal; activation of the adaptive immune system through known processes as antigen presentation; and Acting as a physical and chemical barrier against infectious agents (e.g., epithelial surface, stomach) This includes the intestinal tract. Typically, leukocytes are the cells that perform the actions of the innate immune system. These are white blood cells. These cells include natural killer cells, mast cells, and eosinophils. These include globules, basophils, macrophages, neutrophils, and dendritic cells. These cells are responsible for infection. It functions within the immune system by identifying and eliminating potential pathogens.

[0146] In one aspect, activators of the innate immune response are pattern recognition receptors (PRRs) It is Do.

[0147] In one embodiment, activators of the innate immune response are agonists of pattern recognition receptors (PRRs). It's a strike.

[0148] In one aspect, the activators of the innate immune response are the inducers of type I interferon. Yes. In one aspect, the activator of the innate immune response is recombinant interferon. ru.

[0149] In one embodiment, activators of the innate immune response activate and / or proliferate NK cells. It is an effective inducer. In one embodiment, an "effective inducer" is the activation of NK cells. It refers to activators of the innate immune response that directly induce and / or proliferation.

[0150] In one embodiment, activators of the innate immune response activate dendritic cells and / or... It is an effective inducer of maturation. In one embodiment, an "effective inducer" is defined as the activity of dendritic cells. This refers to activators of the innate immune response that directly induce sexualization and / or maturation.

[0151] In one embodiment, the activator of the innate immune response is type I interferon by dendritic cells. It is an effective inducing factor for dendritic cells. In one embodiment, an "effective inducing factor" is a factor that dendritic cells use. This refers to an activator of the innate immune response that directly induces type I interferon.

[0152] In one embodiment, the activator of the innate immune response is a small molecule or a biopharmaceutical. In one aspect, the activators of the innate immune response are small molecules. The activators of the immune response are biopharmaceuticals.

[0153] In one aspect, the activators of the innate immune response are interferon gene stimulators (S TING agonist, cytosolic DNA sensor (CDS) agonist, Toll-like receptor (TLR) agonist C-type lectin receptor (CLR) agonist, NOD-like receptor (NLR) agonist, RIG-I-like receptor It is a somatic (RLR) agonist or inflammasome-inducing factor.

[0154] In one aspect, the activators of the innate immune response are interferon gene stimulators (S TING agonists, Toll-like receptor (TLR) agonists, or NOD-like receptor (NLR) agonists Yes. In one aspect, the activators of the innate immune response are interferon gene stimulants. It is a STING agonist or a Toll-like receptor (TLR) agonist. In one embodiment, The activators of the natural immune response are interferon gene-stimulating factor (STING) agonists and TLR7. It is an agonist, or a TLR8 agonist.

[0155] In one aspect, the activators of the innate immune response are 3'3'-cGAMP, 2'3'-cGAMP, and 2'3 '-cGAM(PS)2(Rp / Rp), 2'3'-cGAM(PS)2(Rp / Sp), 2'2'-cGAMP, c-di-AMP, 2'3'-c- G-AMP, 2'3'-c-G-AMP(PS)2(Rp / Rp), 2'3'-c-G-AMP(PS)2(Rp / Sp), c-G-GMP, c-G -IMP, HSV-60, ISD, VACV-70, poly(dA:dT), poly(dG:dC), heat-sterilized bacteria, lipog Lican, lipopolysaccharide (LPS), lipoteichoic acid, peptidoglycan (PGN), synthetic lipoprotein, Poly(A:U), Poly(I:C), Monophosphoryl Lipid A (MPLA), GSK1795091, g100, sd-101, mgn 1703, cmp-001, Flagellin (FLA), PolyU, Poly(dT), Gardicimodo, Imiquimod (R837) ), base analogs, adenine analogs, guanosine analogs, purine derivatives, benoazepine analogs Body, imidazoquinoline, thiazoquinoline, loxoribine, reciquimod (R848), dactryci B, Smanilol, N1-Glycinyl[4-((6-amino-2-(butylamino)-8-hydroxy-9H-P Phosphate-9-yl(methyl)benzoyl]spermine (CL307), CL264, CL097, CL075, CL347, CL4 01, CL413, CL419, CL531, CL553, CL572, MEDI9197, MEDI5083, Hypoxanthine, TL8-5 06, PF-4878691, Isatoribin, SM-324405, SM-324406, AZ12441970, AZ12443988, CpG Oligonucleotides, bacterial DNA, beta-glucans, and beta-glucans from fungal and bacterial cell walls. Glucan, γ-D-Glu-mDAP (iE-DAP), Ie-dap derivatives, muramyl dipeptide (MDP), MDP derivatives Body, 5' triphosphate double-stranded RNA, poly(dA:dT), ATP, chitosan, aluminum potassium sulfate, Anhydrous calcium pyrophosphate, silicon dioxide, MurNAc-L-Ala-γ-D-Glu-mDAP (M-TriDAP), Santenone analogs (e.g., DMXAA; badimethan), TREX1 inhibitors, cyclic dinucleotides, LH C165, 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), their derivatives, or pharmaceutically acceptable salts thereof.

[0156] In one embodiment, the activator of the innate immune response is fluorine of any of the above activators. It is a fluorinated derivative. In one embodiment, the activator of the innate immune response is difluorinated cAIMP(c-(2 'FdAMP-2' (FdIMP)). In one embodiment, the activator of the innate immune response is difluorinated. cAIM(PS)2(Rp / Sp). In one embodiment, the activator of the innate immune response is the activation of the above activation It is an O-methylated derivative of one of the factors.

[0157] In one aspect, the activators of the innate immune response are 3'3'-cGAMP, 2'3'-cGAMP, and 2'3 '-cGAM(PS)2(Rp,Rp), 2'3'-cGAM(PS)2(Rp,Sp), 2'2'-cGAMP, c-di-AMP, 2'3'-c- G-AMP, 2'3'-c-G-AM(PS)2(Rp,Rp), 2'3'-c-G-AM(PS)2(Rp,Sp), c-G-GMP, 2'3' -c-ji-GMP, 2'3'-c-ji-GM(PS)2(Rp,Rp), 2'3'-c-ji-GM(PS)2(Rp,Sp), c-ji-IMP, Re Shikimod, CpG oligonucleotide, polyinosine / polycytidic acid, LHC165, GSK-22450 35, RG7854, GS-9620, GS-9688, EMD1201081, PF-3512676, BO-112, RGT-100, MK-1454, SB-11285, NKTR-262, CDX-301, 2'3'-c-G-GMP, cAIMP, cAIM(PS)2(Rp / Sp), or so It is a pharmaceutically acceptable salt.

[0158] In one aspect, the activators of the innate immune response are 3'3'-cGAMP, 2'3'-cGAMP, and 2'3 '-cGAM(PS)2(Rp,Rp), 2'3'-cGAM(PS)2(Rp,Sp), 2'2'-cGAMP, c-di-AMP, 2'3'-c- G-AMP, 2'3'-c-G-AM(PS)2(Rp,Rp), 2'3'-c-G-AM(PS)2(Rp,Sp), c-G-GMP, 2'3' -c-G-GMP, 2'3'-c-G-GM(PS)2(Rp,Rp), 2'3'-c-G-GM(PS)2(Rp,Sp), c-G-IMP, 2' Fluorinated derivatives of 3'-c-di-GMP, cAIMP, cAIM(PS)2(Rp / Sp), or pharmaceutically acceptable derivatives thereof. It is a good salt.

[0159] In one aspect, the activators of the innate immune response are 3'3'-cGAMP, 2'3'-cGAMP, and 2'3 '-cGAM(PS)2(Rp,Rp), 2'3'-cGAM(PS)2(Rp,Sp), 2'2'-cGAMP, c-di-AMP, 2'3'-c- G-AMP, 2'3'-c-G-AM(PS)2(Rp,Rp), 2'3'-c-G-AM(PS)2(Rp,Sp), c-G-GMP, 2'3' -c-G-GMP, 2'3'-c-G-GM(PS)2(Rp,Rp), 2'3'-c-G-GM(PS)2(Rp,Sp), c-G-IMP's O- A methylated derivative, or a pharmaceutically acceptable salt thereof.

[0160] In one aspect, the activators of the innate immune response are 2'3'-cGAMP and 2'3'-c-di-AM(PS). 2(Rp,Rp), MurNAc-L-Ala-γ-D-Glu-mDAP (M-TriDAP), c-di-GMP, or resikimod. In one aspect, the activators of the innate immune response are 2'3'-cGAMP and 2'3'-c-di-AM(PS). 2(Rp,Rp), MurNAc-L-Ala-γ-D-Glu-mDAP (M-TriDAP), or reciquimod. In one embodiment In this context, the activators of the innate immune response are 2'3'-cGAMP, 2'3'-c-di-AM(PS)2(Rp,Rp), Or reximod. In one embodiment, the activator of the innate immune response is 2'3'-c- It is di-AM(PS)2(Rp,Rp) or reximod. In one embodiment, it activates the innate immune response. The factor is cAIMP or its fluorinated derivative. In one embodiment, the activation of the innate immune response The sexualizing agent is difluoride cAIMP.

[0161] In one embodiment, the activator of the innate immune response is 2'3'-cGAMP, or its pharmaceutically It is an acceptable salt. In particular, 2'3'-cGAMP (cyclic [G(2',5')pA(3',5')p]) is endogenous seca It functions as an end messenger and induces a STING-dependent type I interferon response. It is stated that 2'3'-cGAMP also promotes the production of antigen-specific antibodies in mice. It has been shown to be an effective adjuvant for boosting T cell responses. 2'3'-cGAM P performs antiviral functions in the cells in which it is produced, and also through passive diffusion. It can exert its effects on nearby cells by crossing the cell membrane. [ka]

[0162] In one aspect, the activator of the innate immune response is 2'3'-c-di-AM(PS)2(Rp,Rp), and It is a pharmaceutically acceptable salt. 2'3'-c-di-AM(PS)2(Rp,Rp) is a 3'3'-cyclic adenocarcinoma. It is the Rp,Rp-isomer of the 2'3'-bisphosphorothioate analog of nosine monophosphate (c-di-AMP). It is also a Sting agonist. [ka]

[0163] In one aspect, the activator of the innate immune response is cAIMP, its difluorinated derivative, and its Bisphosphorothioate difluoride derivative (cAIM(PS)2(Rp / Sp)), or a pharmaceutically acceptable derivative thereof. It is a capable salt. cAIMP and its derivatives are also STING agonists. [ka]

[0164] In one embodiment, the activator of the innate immune response is a STING agonist, where S TING agonists are cyclic dinucleotides. In one embodiment, cyclic dinucleotides This is disclosed in the United States Patent Application USSN 15 / 234,182, filed on August 11, 2016. This is a cyclic dinucleotide, and the entire contents of this application are incorporated herein by reference. In one embodiment, a cyclic dinucleotide is a U.S. patent filed on December 16, 2014. Any cyclic dinucleotide disclosed in the license application USSN 14 / 362,441, The entire contents of the application are incorporated herein by reference.

[0165] In one aspect, the activator of the innate immune response is MK-1454.

[0166] In one embodiment, activators of the innate immune response are cytosolic DNA sensor (CDS) agonists. It is a agonist. In one embodiment, a CDS agonist is a cyclic GMP-AMP synthase (cGAS) agonist. It's a strike.

[0167] In one aspect, activators of the innate immune response are described in a US patent application filed on December 16, 2013. Any STING agonist or cGAS agonist disclosed in patent application USSN 14 / 653,586 This is a strike, and the entire contents of the said application are incorporated herein by reference. In a certain manner In this context, the activator of the innate immune response is described in the USS Patent Application filed on May 2, 2014. Any STING agonist or cGAS agonist disclosed in 14 / 268,967, and The entire contents of the said application are incorporated herein by reference. In one embodiment, natural immunity The activators of the epidemic response are described in U.S. Patent Application USSN 14 / 787,611, filed on April 29, 2014. Any STING agonist or cGAS agonist disclosed in said application, within the entirety of said application The following is incorporated herein by reference. In one embodiment, the activity of the innate immune response The chemical factor is disclosed in U.S. Patent Application USSN 14 / 908,019, filed on July 31, 2014. Any STING agonist or cGAS agonist that is included in this specification, and the entirety of this application is the same as that of the STING agonist or cGAS agonist. It is used as a reference in the book.

[0168] In one aspect, the activator of the innate immune response is described in a US patent application filed on June 14, 2011. Any STING agonist disclosed in the licensed application USSN 13 / 057,662, and said application The entire contents of this document are incorporated herein by reference. In one embodiment, the innate immune response The activator of is described in US Patent Application USSN 14 / 106,687, filed on December 13, 2013. Any STING agonist disclosed herein, the entire contents of which are referenced herein. This is used as a reference. In one aspect, activators of the innate immune response are... (May 19, 2016) Any STING agonis disclosed in U.S. Patent Application USSN 15 / 035,432 filed in [location] The entire contents of the said application are incorporated herein by reference. Furthermore, the activator of the innate immune response was identified in the international patent application PCT / US201 filed on January 11, 2017. Any STING agonist disclosed in 7 / 013049, and the entirety of said application is subject to the present invention. This is referenced in the details. In one embodiment, the activators of the innate immune response are, Any ST disclosed in international patent application PCT / US2017 / 013066 filed on January 11, 2017 This is an ING agonist, and the entire contents of the said application are incorporated herein by reference. In one aspect, the activator of the innate immune response is an international patent filed on May 18, 2014. Any STING agonist disclosed in application PCT / US2014 / 038525, and all of the said application The contents are incorporated herein by reference. In one embodiment, the activation of the innate immune response The sexualizing factor is disclosed in U.S. Patent Application USSN 13 / 912,960, filed on June 7, 2013. Any STING agonist that is used, and the entire contents of the said application are referenced herein. In one embodiment, an activator of the innate immune response was filed on January 12, 2016. Any STING agonist disclosed in the international patent application PCT / IB2016 / 057265 The entire contents of the said application are incorporated herein by reference.

[0169] In one aspect, the activator of the innate immune response is MurNAc-L-Ala-γ-D-Glu-mDAP(M-Tri M-TriDAP is a pharmaceutically acceptable salt thereof, and is primarily used by Gram-negative bacteria. It is a peptidoglycan (PGN) degradation product found in the intracellular space. It is recognized by sensor NOD1 (CARD4), and to a lower degree by NOD2 (CARD15). Recognition of M-TriDAP by NOD1 / NOD2 is linked to serine / threonine RIP2 (RICK, CARDIAK) kinase. It induces a signaling cascade that includes IKK, which interacts with IKK to activate NF-κB. Furthermore, it leads to the production of inflammatory cytokines such as TNF-α and IL-6. M-TriDAP is NF It induces activation of -κB at a level similar to that of Tri-DAP.

[0170] In one embodiment, the activator of the innate immune response is a TLR7 agonist. In this context, the activator of the innate immune response is a TLR8 agonist. In one embodiment, The activators of the immune response are TLR7 agonists and TLR8 agonists.

[0171] In one aspect, the activators of the innate immune response are immune response modifiers (IRMs).

[0172] In one embodiment, an activator of the innate immune response is described in a US patent application filed on March 22, 1996. Any IRM disclosed in the licensed application USSN 08 / 620,779, and the entire contents of said application are: This is incorporated herein by reference. In one embodiment, an activator of the innate immune response This is disclosed in U.S. Patent Application USSN 08 / 957,192, filed on October 24, 1997. This is an arbitrary IRM, and the entire contents of the said application are incorporated herein by reference. In this aspect, the activator of the innate immune response is described in U.S. Patent Application U filed on March 20, 2000. Any IRM disclosed in .SSN 09 / 528,620, and the entire contents of said application are as described in this specification. This is referenced in the book. In one embodiment, the activators of the innate immune response are 19 Any I disclosed in U.S. Patent Application USSN 06 / 798,385, filed on November 15, 1985 This is a registered trademark, and the entire contents of the said application are incorporated herein by reference. In a certain aspect Furthermore, the activator of the innate immune response is described in the U.S. Patent Application USSN 0 filed on September 8, 1994. Any IRM disclosed in 8 / 303,216, the entire contents of said application are herein by reference. This is used for reference. In one aspect, the activators of the innate immune response were identified on December 11, 1998. Any IRM disclosed in U.S. Patent Application USSN 09 / 210,114 filed on [date], The entire contents of the said application are incorporated herein by reference. In one embodiment, The activator of the immune response is described in U.S. Patent Application USSN 09 / 361,544, filed on July 27, 1999. Any IRM disclosed in said application, and the entire contents of said application are referenced herein. In one aspect, an activator of the innate immune response was filed on October 1, 2004. Any IRM disclosed in the international patent application PCT / US2004 / 032480, which is the IRM of the said application. All of the contents herein are incorporated herein by reference only.

[0173] In one aspect, the activator of the innate immune response is CL307(N1-glycinyl[4-((6-amino -2-(butylamino)-8-hydroxy-9H-purine-9-yl)methyl)benzoyl]spermine), or a pharmaceutically acceptable salt thereof. CL307 is a very potent TLR7 agonist. Titration experiments showed that CL307 is potent even at a concentration of only 20 nM (10 ng / ml) and has a strong NF-κB effect. It has been shown to induce activation. [ka]

[0174] In one embodiment, the activator of the innate immune response is CL264, or its pharmaceutically acceptable It is a beneficial salt. CL264 activates NF-κB and IFN-α in cells expressing TLR7. It induces secretion. CL264 is a TLR7-specific ligand, and even at high concentrations (>10 μg / ml), T It does not stimulate LR8. In HEK293 cells into which TLR7 has been gene-transfected, CL264 is imiquimod It can induce NF-κB activation at a concentration 0.1 μM, which is 5 to 10 times lower than that. [ka]

[0175] In one aspect, the activator of the innate immune response is loxoribine, or its pharmaceutically It is an acceptable salt. Loxoribine is a guanosine derivative at the N7 and C8 positions. They are similar. This nucleoside is a very potent stimulant of the immune system. Loxoribine This activates the innate immune system through TLR7, and this activation requires endosome maturation. Yes. Recognition of loxolibine is limited to TLR7. [ka]

[0176] In one aspect, the activator of the innate immune response is hypoxanthine, or its pharmaceutical It is an acceptable salt. Hypoxanthine is a naturally occurring purine derivative. [ka]

[0177] In one embodiment, the activator of the innate immune response is TL8-506, or its pharmaceutically acceptable It is a possible salt. TL8-506 is an analog of the Toll-like receptor 8 (TLR8) agonist VTX-2337. It is an anezoazepine compound. TL8-506 activates TLR8 more potently than R848 and CL075. TL8-506 induces NF-κB activation in HEK293 cells transfected with TLR8. In this respect, it is approximately 50× and 25× stronger than R848 and CL075, respectively. TL8-506 is a selective agonist of TLR8. [ka]

[0178] In one aspect, the activators of the innate immune response are PF-4878691, isatoribin, and SM-324. 405, SM-324406, AZ12441970, AZ12443988, GSK-2245035, RG7854, GS-9620, LHC165, NK TR-262, GS-9688, VTX-2337, or a pharmaceutically acceptable salt thereof. PF-4878691, i Satoribin, SM-324405, SM-324406, AZ12441970, AZ12443988, GSK-2245035, RG7854 The GS-9620 is a TLR7 agonist. The LHC165 and NKTR-262 are agonists for both TLR7 and TLR8. It is an agonist of the TLR8. GS-9688 and VTX-2337 are TLR8 agonists.

[0179] In one aspect, activators of the innate immune response include dactricib, imiquimod, and garde. Imidazone containing iximod, reximod, smanilol, and their pharmaceutically acceptable salts. It is a quinoline derivative.

[0180] In one embodiment, the activator of the innate immune response is CL097, or its pharmaceutically acceptable It is a highly water-soluble salt. CL097 is a highly water-soluble derivative reximod (≧20 mg / ml). CL097 is It is a ligand for TLR7 and TLR8. It is used in HEK293 cells transfected with TLR7. In general, the concentration was 0.4 μM (0.1 μg / ml), while in HEK293 cells transfected with TLR8, it was 4 μM (1 μg / ml). This induces NF-κB activation. [ka]

[0181] In one embodiment, the activator of the innate immune response is CL075, or its pharmaceutically acceptable It is a beneficial salt. CL075 (3M002) is a thiazoloquinone that stimulates TLR8 in human peripheral blood mononuclear cells. It is a lon derivative. It activates NF-κB to preferentially promote the production of TNF-α and IL-12. It causes. CL075 also induces IFN-α secretion through TLR7, but this is lower. To that extent. In HEK293 cells into which TLR8 has been gene-transfected, the level is 0.4 μM (0.1 μg / In ml, NF-κB activation was induced, and NF-κB was activated in HEK293 cells into which TLR7 had been gene-transfected. Approximately 10 times more CL075 is required for activation. [ka]

[0182] In one embodiment, the activator of the innate immune response is MEDI9197, or its pharmaceutically acceptable It is a possible salt. MEDI9197 (3M052) is an injectable TLR7 and TLR8 agonist. It is an imidazoquinoline immunomodulatory factor (IRM) having a C18 lipid moiety, and when administered It is designed to spread slowly from one area to the next. [ka]

[0183] In one aspect, the activator of the innate immune response is reximod (R848), or its pharmaceutical It is a generally acceptable salt. In particular, reximod is an agent that acts as an immunoassay modifier. It has antiviral and antitumor activity. It is effective against skin lesions (herpes simplex virus). In the treatment of conditions such as those caused by cutaneous T-cell lymphoma, topical gels and It is used as an adjuvant to increase the effectiveness of vaccines. It is used. It has several mechanisms of action, affecting Toll-like receptors 7 (TLR7) and 8 (TLR8). It is an agonist for both and an upregulator of opioid growth factor receptors. [ka]

[0184] In one embodiment, the activator of the innate immune response is a TLR7-selective ante-drug. In one aspect, the activator of the innate immune response is SM-324405, AZ12441970, or the It is a pharmaceutically acceptable salt.

[0185] In one embodiment, the activator of the innate immune response is GS-9620. In one embodiment The activator of the innate immune response is PF-4878691. In one embodiment, the innate immune response The activator is NKTR-262. In one embodiment, the activator of the innate immune response is LHC1 It is 65.

[0186] In one embodiment, the activators of the innate immune response are inflammasome-inducing factors. Inflammasomes are important for the host's defense against infection and endogenous danger signals. They are multimeric protein complexes. They are interleukinocytes, which are pro-inflammatory cytokines. It promotes the secretion of kin (IL)-1β and IL-18, leading to a rapid induction of inflammation known as pyroptosis. It causes cell death in the sexual morphology.

[0187] In one embodiment, the activators of the innate immune response are NLRP3, AIM2, NLRC4, or NLRP1 It is an inducer of the phramosome.

[0188] In one aspect, activators of the innate immune response are, [ka] or a pharmaceutically acceptable salt thereof, where: R 1 H is R 2 Is it H? 1 is a butyl group, R 2 Is it H? 1 H is R 2 is -CO2CH3; or R 1 is It is a chill group, R 2 It is -CO2CH3.

[0189] In one aspect, the activators of the innate immune response are: imidazoquinoline; Midazonaphthyridine; pyrazolopyridine; aryl-substituted imidazoquinolines; 1-alkoxy Compounds having a 1H-imidazo ring system; oxazolo[4,5-c]-quinoline-4-amine; thiazolo[4,5 -c]-quinoline-4-amine; selenazolo[4,5-c]-quinoline-4-amine; imidazonaphthyridine Imidazocinolinamine; 1-substituted, 2-substituted 1H-imidazo[4,5-C]quinoline-4-amine; condensation Cycloalkylimidazopyridine; 1H-imidazo[4,5-c]quinoline-4-amine; 1-substituted 1H- Midazo-[4,5-c]quinoline-4-amine;Imidazo-[4,5-C]quinoline-4-amine;2-ethyl 1H- Imidaz[4,5-c]quinoline-4-amine; olefinic 1H-imidazo[4,5-c]quinoline-4-amine 6,7-dihydro-8-(imidazole-1-yl)-5-methyl-1-oxo-1H,5H-benzo[ij]quinol Lysine-2-carboxylic acid; Pyridoquinoxaline-6-carboxylic acid; 6,7-dihydro-8-(imidazo Lu-1-yl)-5-methyl-1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid; substituted naphth [ij]Quinolidine; Substituted pyridoquinoxaline-6-carboxylic acid; 7-hydroxybenzo[ij]Quino Lysine-2-carboxylic acid derivatives; substituted benzo[ij]quinolidine-2-carboxylic acid; 7-hydroxy- Benzo[ij]quinolidine-2-carboxylic acid; substituted pyrido[1,2,3,-de]-1,4-benzoxazine; te N-methylene malonate ester of trahydroquinoline, or a pharmaceutically acceptable salt thereof.

[0190] In one aspect, the activator of the innate immune response is described in a US patent application filed on August 31, 2016. Any NLRP3 agonist disclosed in the licensed application USSN 15 / 253,215, said application The entire contents of this document are incorporated herein by reference.

[0191] In one embodiment, the activators of the innate immune response are RORγ agonists. The stent binds to and activates RORγ, for example, in a patient or a population of cells. It is an agent that promotes the activity of RORγ by either increasing the expression of RORγ or by other means. The RORγ agonist may be, for example, an organic small molecule, a polypeptide, or a nucleic acid. Such RORγ agonists are mentioned in the literature, for example, in US Patent Application USSN 14 / 398,774; Zhan g et al., Mol. Pharmacol. (2012), Vol. 82, pp. 583-590; and Wang et al., ACS Chem. This was reported in Biol. (2010), Vol. 5, pp. 1029-1034, and each of these is described herein. It is used as reference.

[0192] In one embodiment, the activator of the innate immune response is a RORγ agonist, for example, [ka] and its pharmaceutically acceptable salt.

[0193] In one embodiment, an activator of the innate immune response is described in U.S. Patent Application USSN 14 / 398,774. A general or specific compound described in, for example, formula (I): [ka] A compound of or a pharmaceutically acceptable salt thereof; in the formula: A is aryl, aralkyl, heteroaryl, cycloalkyl, or heterocyclo They are alkyl groups; each of these can optionally and independently be a halogen, hydroxyl, or C. 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, -N(R 4 )(R 5 ), -CO2R 6 , -C(O)R 6 -CN, -C 1~4 Alki Len-C 1~4 Alkoxy, -C 1~4 Alkylene-N(R)4 )(R 5 ), -C 1~4 Alkylene-CO 2R 6 -OC 1~6 Alkylene-N(R) 4 )(R 5 ), -N(R 4 )C(O)-C 1~6 Alkylene-N (R 4 )(R 5 ), -S(O) p C 1~6 Alkyl, -SO2N(R 4 )(R 5 ), -N(R 4 )SO2(C 1~6 Alkyl), -C(O)N(R 4 )(R 5 ), and -N(R 4 )C(O)N(R 4 )(R 5 ) It is substituted with one, two, or three substituents selected from the group; X is -O-[C(R 6 )(R 7 )]-[C(R 6 )2] m -Ψ, -OC(R 6 )2-C(R 6 )(R 7 )-C (R 6 )2-Ψ, -OC(R 6 )2-C(R 6 )(R 7 )-Ψ,-C(R 6 )2-[C(R 6 )(R 7 )]-[C( R 6 )2] m -Ψ, -C(O)-[C(R 6 )(R 7 )]-[C(R 6 )2] m -Ψ, -C(R 6 )2-N(R 8 )- [C(R 6 )(R7 )]-[C(R 6 )2] m -Ψ, -C(R 6 )=N-Ψ, -C(R 6 )2C(R 6 )=N-Ψ , -N=C(R 6 )-Ψ, or -N=C(R 6 )C(R 6 )2-Ψ; where Ψ is a bond to the sulfonamide ring nitrogen atom in formula I; Y is -N(R 2 )(R 3 ) or -O-arylalkyl, where the arylalkyl is optionally and independently halogen, hydroxyl, C 1~6 alkoxy, C 1~6 haloalkoxy, C 1~6 alkyl, C 1~6 haloalkyl, -N(R 4 )(R 5 ), -CN, -CO2-C 1~6 alkyl ), -C(O)-C 1~6 alkyl, -C(O)N(R 4 )(R 5 ), -S(O) p C 1~6 alkyl, -S O2N(R 4 )(R 5 ), and -N(R 4 )SO2(C 1~6 alkyl) selected from the group consisting of; substituted with 1, 2 or 3 substituents selected from; R 1 each independently represents hydrogen, halogen, or C 1~6 alkyl; R​​​​​​​​​​​​​m -heterocyclyl, -C(O)-C 1~6 Alkyl, -C(O)- C 1~6 Alkylene-C 1~6 Alkoxyl, -C(O)-C 1~6 Alkylene-cycloalkyl, taha-C(O)-C 1~6 They are alkylene-heterocycloalkyl; each of these is optionally , independently, halogen, hydroxyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C1 ~6 Alkyl, C 1~6 Haloalkyl, -N(R) 4 )(R 5 ), -CN, -CO2-C 1~6 Alkyl , -C(O)-C 1~6 Alkyl, -C(O)N(R 4 )(R 5 ), -S(O) p C 1~6 Alkyl, -SO 2N(R 4 )(R 5 ), and -N(R 4 )SO2(C 1~6 Selected from the group consisting of alkyl groups , substituted with two or three substituents; R 3 is hydrogen or C 1~6 It is alkyl; R 4 and R 5 Each of these independently, in each case, is either hydrogen or C 1~6 Alki Represents Ru; or R 4 and R 5 Together with the nitrogen atoms to which they are bonded, It forms a heterocyclic ring with 3 to 7 members; R 6 Independently, in each case, hydrogen or C 1~6 Represents alkyl; R 7is hydrogen, hydroxyl, C 1~6 Hydroxyalkyl, C 1~6 Alkyl, C 1~6 Ha Roalkyl, -CO2R 6 , C 1~6 Alkylene-CO2R 6 , C 1~4 Hydroxyalkylene -CO2R 6 , -N(R 4 )(R 5 ), C 1~6 Alkylene-N(R) 4 )(R 5 ), C 1~6 hydroxy Alkylene-N(R) 4 )(R 5 ), -N(R 4 )C(O)R 9 , C 1~6 Alkylene-N(R) 4 )C(O) R 9 , C 1~6 Alkylene-C(O)N(R) 4 )(R 5 ), -N(R 4 )CO2-C 1~6 Alkyl, also or C 1~6 Alkylene-N(R) 4 )(C(O)N(R 4 )(R 5 ) or R 7 is, Hete Rocycloalkyl or C 1~4 It is an alkylene-heterocycloalkyl, where, Terocycloalkyls can optionally and independently be oxo, halogen, hydroxyl, or C. 1~6 a Lu kill, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, and C 1~6 It is substituted with one, two, or three substituents selected from the group consisting of haloalkoxys. ; R8 is hydrogen, C 1~6 Alkyl, or -C(O)-C 1~6 It is alkyl; R 9 is hydrogen, C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkylene-N(R) 4 )(R 5 ), or C 1~6 Alkylene-N(R) 4 )C(O)-C 1~6 It is alkyl; n is 1 or 2; and m and p each independently represent 0, 1, or 2 in their respective cases.

[0194] In one aspect, the activator of the innate immune response is described in a US patent application filed on November 4, 2014. Any RORγ agonist disclosed in patent application USSN 14 / 398,774, and said The entire contents of the application are incorporated herein by reference. In one embodiment, innate immune response The activator of the answer is described in US Patent Application USSN 15 / 120,798, filed on August 23, 2016. Any RORγ agonist disclosed herein, the entirety of the said application is herein by reference. It will be used as reference.

[0195] In one embodiment, the activators of the innate immune response are RIG-I-like receptor (RLR) agonists. In one embodiment, the activator of the innate immune response is RGT-100.

[0196] Cytokine The drug delivery composition and device may contain cytokines. Cytokines are fine A broad category of small proteins (approximately 5–20 kDa) that are important in cell signaling. —Their release has an effect on the behavior of the surrounding cells. In autocrine signaling, parasecrine signaling, and endocrine signaling They are involved as immunomodulators. As cytokines, chemokines and interferons These include interleukins, lymphokines, and tumor necrosis factors. These include immune cells such as macrophages, B lymphocytes, T lymphocytes, and mast cells, as well as internal It is produced by a wide range of cells, including cortical cells, fibroblasts, and various stromal cells. Cytokines act through receptors and play an important role in the immune system. Cytokines are involved in the body's fluids. It regulates the balance between sex-based immune responses and cell-based immune responses, and the maturation of specific cell populations. They control proliferation and responsiveness. Some cytokines, in complex ways, control others. Cytokines enhance or inhibit the action of itokines. Cytokines are involved in the host's response to infection and immunity. It is important in disease response, inflammation, trauma, sepsis, cancer, and reproduction.

[0197] Furthermore, the immune-stimulating functions of many cytokines and chemokines are fully utilized. To enable this, the method of delivery, administration and scheduling, as well as toxicity-related aspects, It is currently known in this field that we must address the following problems.

[0198] In one embodiment, cytokines include IL-1, IL-1α, IL-1β, IL-2, and IL-2 supercytokines. IL-6, IL-7, IL-9, AM0010, IL-12, IL-15, IL-15 Super Agonist, ALT-803, NI Z985, IL-16, IL-18, IL-21, IL-21 Super Agonist, Denenikokin, IL-21 Super Agonist antibodies, IFN-α, IFN-β, IFN-γ, TNF-α, GM-CSF, cytokine fusions, RG74 61, RG7813, M9241, NKTR-214, NKTR-255, BMS-982470, BG-00001, Flt3L, or CDX-30 It is 1.

[0199] In one embodiment, cytokines include ALT-803, NIZ985, Denenikokin, RG7461, and RG781. 3. M9241, IFN-α, IFN-β, or IFN-γ.

[0200] In one embodiment, the cytokine is an IL-15 superagonist or IL-21. In one embodiment, the cytokine is an IL-15 superagonist.

[0201] In one aspect, cytokines include IL-15 superagonists, IL-21, IFN-α, and IFN- These are β, IFN-γ, CCL4, CCL5, CXCL9, or CXCL10. In one embodiment, cyto The ion is an IL-15 superagonist, IFN-α, IFN-β, or IFN-γ. In some embodiments, The cytokines involved are IL-15 superagonists or IFN-α.

[0202] IL-15 (interleukin-15) is a cytokine that is structurally similar to IL-2, and is used by It is secreted by mononuclear phagocytic cells after infection by Russ. IL-15's main role is in virus It induces the proliferation of natural killer cells, which kill cells infected with Rus. The combination of IL-15 and soluble IL-15Rα is called an IL-15 superagonist (IL-15sa). It forms a complex that has higher biological activity than IL-15 alone. IL-15sa is NK And due to its ability to selectively proliferate memory CD8+T (mCD8+T) lymphocytes, it is an antitumor agent. It is also an antiviral agent.

[0203] In one embodiment, cytokines are publicly released as ALT-803, an IL-15 superagonist. It is a cognitive IL-15 superagonist. ALT-803 induces the proliferation of memory CD8+ T cells, It upregulates receptors involved in innate immunity, secretes interferon-γ, and stimulates antigenicity. It is thought that in the absence of [the substance], it acquires the ability to kill malignant cells. Therefore, ALT-80 3 promotes the proliferation and activation of memory CD8+ T cells, while also giving them potent anti-cancer properties. It can be converted into innate immune effector cells that exhibit activity. ALT-803 is an IL-15 mutation It is a fusion protein of the body and the IL-15Rα / Fc complex, and has recently been found to be a direct immunomodulator. Clinical trials have begun. ALT-803 shows a >25-fold enhancement in biological activity compared to IL-15. show.

[0204] In one embodiment, the cytokine is NIZ985 (hetIL-15). The study investigated the administration of hetIL-15. This promotes increased tumor infiltration and retention of CD8+ T cells, including tumor-specific T cells, and CD8+ / T This indicates that it can lead to an increase in the reg ratio. Tumor-resistant CD8+ T cells are effector cells. It exhibits the characteristics of increased proliferation (Ki67+) and high cytotoxicity (granzyme B+), and is particularly characterized by It is characterized. In the absence of hetIL-15, a smaller population of tumor-infiltrating T cells exhibits high retinal activity. Bell's fatigue marker PD-1 is shown, which potentially limits their anti-cancer efficacy. The provision of hetIL-15 leads to a significant decrease in PD-1 lymphocyte expression, resulting in an exhausted phenotype. One potential mechanism regarding this may be mitigated. Preclinical cancer research suggests that ef is more important than regulatory cells. An approach to tumor immunotherapy to promote the development of an antitumor response by favoring the receptor. We support the use of hetIL-15 in the region.

[0205] In one aspect, the cytokine is interferon-alpha (IFN-α). Proteins are produced by white blood cells. They are primarily used in the innate immune response to viral infections. It contributes to the answer.

[0206] In one aspect, the cytokine is interferon-beta (IFN-β). IFN-β is, It contains proteins produced by fibroblasts and is involved in the innate immune response. IFN-β is a protein produced by fibroblasts. It stimulates both clophages and NK cells to trigger an antiviral response, and also affects tumors. In contrast, it is active. In mice, IFN-β inhibits immune cells from producing growth factors. It harms, thereby slowing tumor growth and generating blood vessels that allow other cells to produce growth factors. This inhibits tumor angiogenesis, thereby blocking tumors from connecting to the vascular system. To obstruct.

[0207] In one aspect, the cytokine is interferon-gamma (IFN-γ). IFN-γ, Type II interferons are cytokines useful for innate and adaptive immunity. IFN-γ is an important activator of macrophages and a major histocompatibility antigen (M) of class II. It is an inducer of HC) molecule expression. In vitro studies of IFN-γ in cancer cells are extensive. The result is that proliferation is inhibited, or generally induced by apoptosis, but sometimes It exhibits antiproliferative activity of IFN-γ, which leads to cell death induced by phagocytosis. Clinical administration has resulted in improved survival rates for patients with ovarian cancer, bladder cancer, and melanoma. .

[0208] In one aspect, cytokines are chemokines. Chemokines are small sites They belong to the kine family. The main role of chemokines is chemical attraction, which guides cell migration. It acts as a substance. Some chemokines are immune during the process of immune surveillance. It controls disease-related cells, for example, directing lymphocytes towards lymph nodes and in those tissues. By interacting with existing antigen-presenting cells, it screens for pathogen invasion. To enable this. These are known as homeostatic chemokines, and their source. They are produced and secreted without requiring cell stimulation. Some chemokines are produced To play a role in life, to promote angiogenesis (proliferation of new blood vessels), or to affect cells It guides cells to tissues that provide specific signals crucial for cell maturation. Gout is an inflammatory disease caused by bacteria, viruses, and other agents that cause damage to the body, such as those that trigger gout. In response to silica or uric acid crystals, it is released from various cells. The release of these is often stimulated by pro-inflammatory cytokines such as interleukin-1. Inflammatory chemokines primarily function as chemotaxis for white blood cells, monocytes, Neutrophils and other effector cells are recruited 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 promote the release of many different cell types, affecting the innate and adaptive immune systems. It helps guide the cells of both systems.

[0209] Furthermore, in order to enable the full utilization of the immunostimulatory functions of many chemokines We address issues related to delivery methods, dosage and scheduling, as well as toxicity. It is currently known in that field that this must be the case.

[0210] In one embodiment, chemokines are CCL1, CCL2, CCL3, CCL4, CCL5, CCL17, CCL19, CC These are L21, CCL22, CXCL9, CXCL10, CXCL11, CXCL13, CXCL16, or CX3CL1.

[0211] Activators of adaptive immune responses The drug delivery composition and device may contain one or more adaptive immune response activators. stomach.

[0212] The adaptive immune response system, also known as the acquired immune system, is a lower-level system of the entire immune system, and is highly advanced. Systemic cells specialized for eliminating pathogens, and processes that remove pathogens or prevent their proliferation. It includes. The adaptive immune system is one of the two major immune strategies found in vertebrates. One is the innate immune system (the other being the natural immune system). Adaptive immunity follows the initial response to a specific pathogen. This creates an immunological memory, resulting in an enhanced response to subsequent encounters with that pathogen. This process of acquired immunity is the basis of vaccination. Similar to the innate immune system, adaptive The immune system includes components of humoral immunity and cell-mediated immunity. Unlike the adaptive immune system, the adaptive immune system is highly specific to particular pathogens.

[0213] The adaptive immune response system is the system that detects when a pathogen escapes the innate immune response and reaches an antigen threshold level, and then dendritic... It is induced when a "stranger" or "danger" signal is generated that activates cells. The primary function of the immune system is specific to the presence of "self" during the antigen presentation process. Recognition of "non-self" antigens; individualized intervention to eliminate specific pathogens or pathogen-infected cells. (tailored) Occurrence of a response; and the pathogen's reaction of memory B cells and memory T cells This includes the development of immunological memory, which is "remembered" throughout the process.

[0214] Useful for activating adaptive immune response systems (e.g., activating therapeutic anti-tumor immunity). One approach is to block immune checkpoints. Immune checkpoints are To minimize collateral tissue damage, self-tolerance is maintained, and physiological processes in peripheral tissues are affected. Physically incorporated into the immune system, which is important for regulating the duration and amplitude of the holistic immune response. This refers to many hardwired inhibitory pathways. Tumors can disrupt specific immune checkpoint pathways. In particular, incorporating it as a major mechanism of immune resistance against T cells specific to tumor antigens. Many immune checkpoints are initiated by ligand-receptor interactions, therefore These can be easily blocked by antibodies, or by recombinant ligand or receptor. It can be controlled by its morphology. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibody is this It was the first immunotherapy drug in its class to receive FDA approval (ipilimumab). Blocking of further immune checkpoint proteins such as Gram cell death protein 1 (PD-1) Prior clinical findings from drug-based therapies present a wide range of diverse opportunities for enhancing antitumor immunity, and This demonstrates the potential to create a durable clinical response.

[0215] PD-1 plays a role in downregulating the immune system by inhibiting the activation of T cells, This then reduces autoimmunity and promotes self-resistance. The inhibitory effect of PD-1 is in the lymph nodes. While promoting apoptosis (programmed cell death) in antigen-specific T cells, simultaneously controlling A dual mechanism that reduces apoptosis in suppressor T cells. This is achieved through PD-1 inhibitors (e.g., anti-P), which are a new class of therapeutic agents that block PD-1. D-1 antibodies activate the immune system to attack tumors, and therefore several types It is used to treat [the condition]. In addition, antibodies against programmed death ligand 1 (PD-L1) are indicated. It provides an effect similar to that of PD-1-targeting antibodies in activating the immune response. Therefore, compositions and devices containing anti-PD-L1 antibodies are similar to those containing anti-PD-1 antibodies. It is expected to provide therapeutic effects.

[0216] In one embodiment, the activators of the adaptive immune response are small molecules. In one embodiment, The activators of the adaptive immune response are biological agents (biologic). In one aspect, A biological agent is a protein. In one aspect, a biological agent is an antibody or its f It is a lagment. In one aspect, a biological drug is a nucleic acid that codes for a protein. be.

[0217] In one aspect, activators of the adaptive immune response include anti-PD-1 antibodies, anti-PD-L1 antibodies, and anti-CTLA- 4 antibodies, anti-TIM3 antibody, anti-OX40 antibody, anti-GITR antibody, anti-LAG-3 antibody, anti-CD137 antibody, anti-CD3 antibody, Anti-CD27 antibody, anti-CD28 antibody, anti-CD28H antibody, anti-CD30 antibody, anti-CD39 antibody, anti-CD40 antibody, anti-CD43 Antibodies, anti-CD47 antibodies, anti-CD48 antibodies, anti-CD70 antibodies, anti-CD73 antibodies, anti-CD96 antibodies, anti-CD123 antibodies, Anti-CD155 antibody, anti-CD160 antibody, anti-CD200 antibody, anti-CD244 antibody, anti-ICOS antibody, anti-TNFRSF25 antibody, Anti-TMIGD2 antibody, anti-DNAM1 antibody, anti-BTLA antibody, anti-LIGHT antibody, anti-TIGIT antibody, anti-VISTA antibody, anti- HVEM antibody, anti-Siglec antibody, anti-GAL1 antibody, anti-GAL3 antibody, anti-GAL9 antibody, anti-BTNL2 (Butilov anti-B7-H3 antibody, anti-B7-H4 antibody, anti-B7-H5 antibody, anti-B7-H6 antibody, anti-KIR antibody, anti-LI antibody R antibody, anti-ILT antibody, anti-CEACAM1 antibody, anti-CEACAM5 antibody, anti-CEACAM6 antibody, anti-MICA antibody, anti-MIC B antibody, anti-NKG2D antibody, anti-NKG2A antibody, anti-A2AR antibody, anti-C5aR antibody, anti-TGFβ antibody, anti-TGFβR antibody body, anti-CXCR4 antibody, anti-CXCL12 antibody, anti-CCL2 antibody, anti-IL-10 antibody, anti-IL-13 antibody, anti-IL-23 antibody Anti-phosphatidylserine antibody, anti-neutropyrin antibody, anti-GalCer antibody, anti-HER2 antibody, Anti-VEGFA antibody, anti-VEGFR antibody, anti-EGFR antibody, anti-Tie2 antibody, anti-CCR4 antibody, or anti-TRAIL-DR5 It is an antibody.

[0218] In one embodiment, the activator of the adaptive immune response is one of the antibodies listed above. It is a lagment. In one embodiment, the activators of the adaptive immune response are the anti- It is one of the humanized forms of the body. In one embodiment, the activator of the adaptive immune response is on It is a single chain of one of the antibodies listed. In one embodiment, the activator of the immune response is , any of the multimerized forms of the antibodies listed above (e.g., dimeric IgA molecules, pentavalent IgM molecules) That is the case.

[0219] In one embodiment, the activators of the adaptive immune response are anti-PD-1 antibodies, agonists, and anti-CD137 antibodies. The body, agonist anti-CD40 antibody, anti-CTLA-4 antibody, anti-LAG-3 antibody, anti-TIM3, or a combination thereof. It is a combination. In one embodiment, the activator of the adaptive immune response is an anti-PD-1 antibody or an anti-CT antibody. It is an LA-4 antibody. In one embodiment, the activator of the adaptive immune response is an anti-PD-1 antibody. In one embodiment, the activator of the adaptive immune response is an anti-CTLA-4 antibody. Therefore, the activator of the adaptive immune response is an agonist anti-CD137 antibody. In one embodiment, The activator of the adaptive immune response is the anti-LAG-3 antibody. In one embodiment, the adaptive immune response The activator is an anti-TIM3 antibody.

[0220] In one aspect, the activators of the adaptive immune response are pembrolizumab, nivolumab, and pi. Dilizumab, ipilimumab, tremelimumab, durvalumab, atezolizumab, ave Lumab, PF-06801591, Utomilumab, PDR001, PBF-509, MGB453, LAG525, AMP-224, INCSHR1210, INCAGN1876, INCAGN1949, Samalizumab, PF-05082566, Ureruma B, Lililumab, Rurizumab, BMS-936559, BMS-936561, BMS-986004, BMS-986012, BMS- 986016, BMS-986178, IMP321, IPH2101, IPH2201, IPH5401, IPH4102, IPH4301, IPH52, IPH53, varlilumab, urocuprumab, monalizumab, MEDI 0562, MEDI0680, MEDI1873, MEDI6383, MEDI6469, MEDI9447, AMG228, AMG820, CC-90002 , CDX-1127, CGEN15001T, CGEN15022, CGEN15029, CGEN15049, CGEN15027, CGEN15052, C GEN15092, CX-072, CX-2009, CP-870893, lucatumumab, dasetuzumab, C hi Lob 7 / 4, RG6058, RG7686, RG7876, RG7888, TRX518, MK-4166, IMC-CS4, Emakuzu Mab, trastuzumab, pertuzumab, obinutuzumab, kabilizumab, margexi Mab, enoblituzumab, mogamulizumab, panitumumab, carlumab Ramucirumab, bevacizumab, rituximab, cetuximab, fresolimmab, denox Mab, MGA012, AGEN1884, AGEN2034, LY3300054, JTX-4014, Tepirizumab, FPA150, PF- 04136309, PF-06747143, AZD5069, GSK3359609, FAZ053, TSR022, MBG453, REGN2810, RE GN3767, MOXR0916, PF-04518600, RO7009789, BMS986156, GWN323, JTX-2011, NKTR-214 These are GSK3174998, DS-8273a, NIS793, or BGB-A317.

[0221] In one aspect, the activators of the adaptive immune response are pembrolizumab, nivolumab, and pi. Dilizumab, Ipilimumab, Tremelimumab, Durvalumab, Atezolizumab, REGN These are 2810, MGA012, AGEN1884, AGEN2034, LY3300054, JTX-4014, or avelumab.

[0222] In one aspect, the activator of the adaptive immune response is an antibody mime or antibody fusion. .

[0223] In one embodiment, the activator of the adaptive immune response is a bispecific antibody. In this context, the bispecific antibody is RG7802 (an antibody targeting carcinoembryonic antigen (CEA) and the 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 (bispecific monoclonal antibody targeting FAP and DR5), ERY974 (CD3 and GR (Bispecific monoclonal antibody targeting lipican-3), MGD012 (targeting PD-1 and LAG-3) (Bispecific monoclonal antibody targeting CD3 and CEA), AMG211 (Bispecific monoclonal antibody targeting CD3 and CEA) T cell inducing antibody (bispecific T cell engager), MEDI573 (bispecific T cell engager targeting IGF1 and IGF2) (Heavily specific monoclonal antibody), MEDI565 (bispecific monoclonal antibody targeting CD3 and CEA) (A one-body antibody), FS17 (target undisclosed), FS18 (targets LAG3 and undisclosed target) (Target bispecific monoclonal antibody), FS20 (undisclosed target), FS22 (disclosed (Target not specified), FS101 (bispecific monoclonal antibody targeting EGFR and HGF), FS1 17 (undisclosed target), FS118 (bispecific monoclonal targeting LAG3 and PD-L1) Monoclonal antibody), RO6958688 (bispecific monoclonal antibody targeting CD3 and CEA), MCLA -128 (bispecific monoclonal antibody targeting HER2 and HER3), M7824 (PD-L1 and T MGD009 (a bifunctional fusion protein that targets GFβ), which recognizes both B7-H3 and CD3. This is either a t-type antibody or MGD013 (a bispecific PD-1 and LAG-3 antibody).

[0224] In one embodiment, the activator of the adaptive immune response is an antibody-drug conjugate. In this study, the antibody-drug conjugates were trastuzumab emtansine and inotuzumab ozogamycin. Shin, PF-06647020, PF-06647263, PF-06650808, RG7596, RG7841, RG7882, RG7986, DS- 8201, ABBV-399, Glembatumumab vedotin, Inotuzumabu Zogamicin, MEDI4276, or a pharmaceutically acceptable salt thereof.

[0225] In one embodiment, the activators of the adaptive immune response are small molecules. In one embodiment, Small molecules include IDO inhibitors, TGFβR inhibitors, BRAF inhibitors, KIT inhibitors, A2aR inhibitors, and Tie2 inhibitors. Arginase inhibitors, iNOS inhibitors, HIF1α inhibitors, STAT3 inhibitors, PGE2 inhibitors, PDE5 inhibitors Harmful agents, RON inhibitors, mTOR inhibitors, JAK2 inhibitors, HSP90 inhibitors, PI3K-AKT inhibitors, β-cateni β inhibitors, GSK3β inhibitors, IAP inhibitors, HDAC inhibitors, DNMT inhibitors, BET inhibitors, COX2 inhibitors PDGFR inhibitors, VEGFR inhibitors, BCR-ABL inhibitors, proteasome inhibitors, angiogenesis inhibitors MEK inhibitors, BRAF+MEK inhibitors, pan-RAF inhibitors, EGFR inhibitors, PARP inhibitors, glutamin These are enzyme inhibitors, WNT inhibitors, FAK inhibitors, ALK inhibitors, CDK4 / 6 inhibitors, or FGFR3 inhibitors. .

[0226] In one embodiment, the small molecule is celecoxib, sunitinib, imatinib, vemuraphen. B, dabrafenib, bortezomib, vorinostat, pomalidomide, thalidomide, le Nalidomide, Epacadostat, Indoximod, GDC0919, BMS986205, AZD8055, AZD46 35, CPI-444, PBF509, LCL161, CB-839, CB-1158, FPA008, BLZ945, IPI-549, Pexida Rutinib, garnicertib, virinapant, trametinib, cobimetinib, binimetinib ensartinib, gefitinib, pazopanib, sorafenib, nintedanib, SYM004, Beriparib, Olaparib, BGB-290, Everolimus, LXH254, Azacitidine, Decitabine Guadecitabine, RRX001, CC486, Romidepsin, Entinostat, Panobinostat Tamoxifen, ibrutinib, idelalisib, capmatinib, selumetinib, ave Maciclib, Parbociclib, Glasdevib, Enzalutamide, AZD9150, PF-06840003, SRF231, Hu5F9-G4, CC-900002, TTI-621, WNT974, BGJ398, LY2874455, or their pharmaceuticals It is a generally acceptable salt.

[0227] Further treatments The drug delivery composition and device may contain further therapeutic agents.

[0228] In one embodiment, the drug delivery composition and device are macrophage effectors It may also contain functional modifiers. Macrophages are immunodegenerative cells derived from circulating monocytes. Macrophages are cells that are present in all tissues and are involved in many stages of disease. They play a dual role in this, and there they can promote tumor growth, but also Macrophages can also act as important immune effectors for therapeutic antibodies. They express Fcγ receptors, and these receptors are involved in tumors through antibody-dependent phagocytic processes. It has the ability to destroy. Numerous studies have shown that the phagocytic action of macrophages can treat cancer. This indicates that this is the primary mechanism of action for many approved antibodies. Macro-level approaches to therapeutic antibodies, including the exploration of new targets and the development of enhanced antibodies. Numerous approaches are being studied to enhance the phage response. Macrophage The response to antibody therapy is also due to engineered Fc variants, bispecific antibodies, or antibodies- Macrophages can be enhanced by drug conjugates. Macrophages are an effector in cancer immunotherapy. —This demonstrates success as a result.

[0229] In one aspect, modifiers of macrophage effector function are myeloid-derived supplements. It is a modifier of suppressor myeloid cells, including lesser cells (MDSCs). In one embodiment, Modifiers of the effector function of macrophages kill macrophages and / or MDSCs. It can be damaged, depleted, or augmented. In one embodiment, Mac Modifiers of the effector function of lophages include anti-CD40 antibodies, anti-CD47 antibodies, anti-CSF1 antibodies, and or anti-CSF1R antibodies. In one embodiment, modification of the effector function of macrophages. The factors are SRF231, Hu5F9-G4, CC-900002, or TTI-621 (anti-CD47 antibody). In a certain embodiment In this study, the modifying factor for the effector function of macrophages is MCS-110 (anti-CSF1 antibody). In one aspect, the modifiers of macrophage effector function are FPA008, RG7155 These are IMC-CS4, AMG820, or UCB6352 (anti-CSF1R antibody). In one embodiment, macroph The modifier of the effector function of phagnum is a small molecule inhibitor of CSF1R. In a certain manner The modifiers for the effector function of macrophages are BLZ945, GW2580, or PLX3397 (CS It is a small molecule inhibitor of F1R. In one embodiment, it modifies the effector function of macrophages. The inhibitors are BTK inhibitors, ITK inhibitors, PI3Kγ inhibitors, or PI3Kδ inhibitors. In some embodiments, In this context, the modifying factor of the effector function of macrophages is one in the composition or device. One or more activators of the adaptive immune response may be replaced.

[0230] In one embodiment, the drug delivery composition and device further contain an oncolytic virus That's fine. In one embodiment, oncolytic viruses include, but are not limited to, Herpes simplex virus (e.g., HSV1716, OncoVex GM-CSF); adenovirus (e.g., H1 01, Onyx-15); poliovirus (e.g., PV1(RIPO)); reovirus (e.g., reolisin) (reolysin); Seneca virus (e.g., NTX-010, SVV-001); Rigvir virus; Marabau virus Examples include viruses; measles; Newcastle disease virus; vaccinia; or ECHO virus. ru.

[0231] In one embodiment, drug delivery compositions and devices contain radioisotopes (e.g., molecular isotopes) They may also be included as part of or on the beads. In one embodiment, radioactive isotopes These are yttrium-90, palladium-103, iodine-125, cesium-131, or iridium-19 The answer is 2.

[0232] In one embodiment, the drug delivery composition and device may further contain a chemotherapeutic agent. i. In one aspect, the following are examples of chemotherapeutic agents, though not limited to these. Anti-estrogen agents (e.g., tamoxifen, raloxifene, and megestrol) LHRH agonists (e.g., goserelin and leuprolide), antiandrogens (e.g., (flutamide and bicalutamide), photodynamic therapy (e.g., verteporfin (vertopo rfin)(BPD-MA), phthalocyanine, photosensitizer Pc4, and demethoxy-hypocrelin A(2BA-2 -DMHA), Nitrogen mustard (e.g., cyclophosphamide, ifosfamide, to (Lophosfamide, chlorambucil, estramustine, and melphalan), nitroso Urea (e.g., carmustine (BCNU) and lomustine (CCNU)), alkyl sulfonates ( For example, busulfan and treosulfan), triazenes (for example, dacarbazine and (and temozolomide), platinum-containing compounds (e.g., cisplatin, carboplatin and oxal). Liplatin), vinca alkaloids (e.g., vincristine, vinblastine, vindecyl vitreous (Panaxyl sulfate and vinorelbine), taxoids (e.g., paclitaxel, or nanoparticle albumin) Calcium-conjugated paclitaxel (ABRAXANE), docosahexaenoic acid-conjugated paclitaxel (DHA- Paclitaxel (Taxoprexin), polyglutamate-bound paclitaxel (PG-paclitaxel) Cell, paclitaxel polygrumex, CT-2103, XYOTAX), tumor-activating prodrug (TAP )ANG1005 (Angiopep-2 bound to 3 molecules of paclitaxel), Paclitaxel-EC-1 (erbB2 approved) Paclitaxel conjugated to the peptide EC-1, and glucose-conjugated paclitaxel For example, 2-paclitaxel methyl 2-glucopyranosyl succinate; docetaxel, ta Paclitaxel equivalents such as xol), epipodophilin (e.g., etoposide, phosphate) Etoposide, Teniposide, Topotecan, 9-Aminocamptothecin, Camptoirinotecan , irinotecan, cristol and mitomycin C), antimetabolites, DHFR inhibitors (e.g.) For example, methotrexate, dichloromethotrexate, trimethotrexate and edat Lexate), IMP dehydrogenase inhibitors (e.g., mycophenolic acid, thiazophrine, Ribavirin and EICAR), ribonucleotide reductase inhibitors (e.g., hydroxy Urea and deferoxamine), uracil analogs (e.g., 5-fluorouracil (5-FU), Phloxuridine, doxifluridine, larcitrexed, tegafur-uracil and Capecitabine), cytosine analogs (e.g., cytarabine (ara C), cytosine arabinoside) (and fludarabine), purine analogs (e.g., mercaptopurine and thioguanine), Tamine D3 analogs (e.g., EB 1089, CB 1093 and KH 1060), isoprenylation inhibitors (e.g.) (For example, lovastatin), dopaminergic neurotoxins (e.g., 1-methyl-4-phenylpyridinium) Ions), cell cycle inhibitors (e.g., staurosporine), actinomycin (e.g., activ) Tinomycin D, Dactinomycin), Bleomycin (e.g., Bleomycin A2, Bleomycin A2, Bleomycin A2) Omycin B2 and peplomycin), anthracyclines (e.g., daunorubicin, d Xorubicin, pegylated liposomal doxorubicin, idarubicin, epirubicin, piral Bicin, zolubicin, and mitoxantrone), MDR inhibitors (e.g., verapamil), Ca 2+ AT Pase inhibitors (e.g., thapsigardin), oblimersen, gemcitabine, carminomexin Leucovorin, pemetrexed, cyclophosphamide, dacarbazine, procarbazine Prednisolone, dexamethasone, campathecin, plicamycin, Asparaginase, aminopterin, metopterin, porphyromycin, melphalan leurosidine, leurosine, chlorambucil, trabectezi Procarbazine, Discodermorid, Carminomycin, Aminopterin, Hexa Methylmelamine and pharmaceutically acceptable salts thereof.

[0233] In one embodiment, the chemotherapeutic agent is an immunomodulatory chemotherapeutic agent. Chemotherapy agents have known immunomodulatory functions (for example, induction of immunogenic cell death or (This is the depletion of immunosuppressive regulatory immune cells). In one aspect, chemotherapy agents are conventional cancer cells Not for use as a cytotoxic chemotherapeutic agent specific to [unspecified], but rather for its immunotherapeutic properties. , included in drug delivery compositions and devices. In one embodiment, the drug delivery composition The device does not contain chemotherapeutic agents. In one embodiment, the drug delivery composition and the device The product does not contain cytotoxic agents.

[0234] In one embodiment, the drug delivery composition and device may further comprise a target agent. In one embodiment, target agents include, but are not limited to, the following: IDO inhibitors Harmful agents, TGFβR inhibitors, arginase inhibitors, iNOS inhibitors, HIF1α inhibitors, STAT3 inhibitors, C SF1R inhibitors, PGE2 inhibitors, PDE5 inhibitors, RON inhibitors, mTOR inhibitors, JAK2 inhibitors, HSP90 inhibitors Drugs, PI3K-AKT inhibitors, β-catenin inhibitors, GSK3 inhibitors, IAP inhibitors, HDAC inhibitors, DNMT inhibitors Harmful agents, BET inhibitors, A2AR inhibitors, BRAF+MEK inhibitors, pan-RAF inhibitors, PI3Kγ inhibitors, PI3Kδ Inhibitors, EGFR inhibitors, VEGF inhibitors, PARP inhibitors, glutaminase inhibitors, BTK inhibitors, ITK Inhibitors, WNT inhibitors, FAK inhibitors, ALK inhibitors, CDK4 / 6 inhibitors, or FGFR3 inhibitors.

[0235] In one embodiment, the targeting agents include, but are not limited to, the following: Tinib, thalidomide, lenalidomide, tyrosine kinase inhibitors (e.g., axitinib) AG013736), Bosutinib (SKI-606), Cedilanib (RECENTINTM, AZD2171), Dasatinib (SPRY CEL (registered trademark, BMS-354825), erlotinib (TARCEVA (registered trademark)), gefitinib (IRESSA (Registered Trademark), Imatinib (Gleevec (Registered Trademark), CGP57148B, STI-571), Lapatinib (TYKER B (registered trademark), TYVERB (registered trademark), Restaurtinib (CEP-701), Neratinib (HKI-272), Nilotinib (TASIGNA®), semaxanib (semaxinib, SU5416), Nitinib (SUTENT®, SU11248), Toceranib (PALLADIA®), Vandethani (ZACTIMA®, ZD6474), batalanib (PTK787, PTK / ZK), trastuzumab (HERCEP) TIN (registered trademark), bevacizumab (AVASTIN (registered trademark)), rituximab (RITUXAN (registered trademark)) , cetuximab (ERBITUX®), panitumumab (VECTIBIX®), ranivizma Lucentis (registered trademark), Nilotinib (TASIGNA (registered trademark)), Sorafenib (NEXAVAR (registered trademark)) Trademarks)), everolimus (AFINITOR®), alemtuzumab (CAMPATH®), Mutuzumab ozogamicin (MYLOTARG®), Temsirolimus (TORISEL®) ENMD-2076, PCI-32765, AC220, Dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOK TM), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BI BF 1120 (VARGATEF (registered trademark)), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-69015 4. CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, and / or XL228), proteasome inhibitors (e.g., bortezomib (VELCADE)), mTOR inhibitors (e.g., Rapamycin, temsirolimus (CCI-779), everolimus (RAD-001), ridafololimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235 (Novartis), BGT226 (Norvartis), XL765 (Sanofi Aventis), PF-4691502 (Pfizer), GDC0980 (Genetech), SF1126 (Semafoe) and OS I-027(OSI), Epacadostat, Indoximod, GDC0919, BMS986205, AZD4635, CPI- 444, PBF509, LCL161, CB-839, CB-1158, FPA008, BLZ945, IPI-549, pexidartinib Garnicertib, virinapant, trametinib, dabrafenib, vemurafenib, ko Bimetinib, Binimetinib, Ensartinib, Pazopanib, Nintedanib, SYM004, Beryl Parib, Olaparib, BGB-290, LXH254, Azacitidine, Decitabine, Guadecitabine, R RX001, CC486, Romidepsin, Entinostat, Vorinostat, Panobinostat, Tamoxifen, ibrutinib, idelalisib, capmatinib, selumetinib, abemasi Crib, Parbocicrib, Glasdegib, Enzalutamide, AZD9150, PF-06840003, SRF2 31, Hu5F9-G4, CC-900002, TTI-621, WNT974, BGJ398, LY2874455, anti-Tie2 antibody, or That pharmaceutically acceptable salt.

[0236] Embodiments of drug delivery compositions and devices In one embodiment, the drug delivery composition and device are a hydrogel and an anti-inflammatory agent. Includes pathway inhibitors.

[0237] In one embodiment, the drug delivery composition and device are a hydrogel, an inflammation-inducing pathway This includes inhibitors and activators of the innate immune response.

[0238] In one embodiment, the drug delivery composition and device are a hydrogel, an inflammation-inducing pathway It includes inhibitors, activators of the innate immune response, and further activators of the innate immune response.

[0239] In one embodiment, the drug delivery composition and device are a hydrogel, an inflammation-inducing pathway This includes inhibitors, activators of the innate immune response, and cytokines.

[0240] In one embodiment, the drug delivery composition and device are a hydrogel, an inflammation-inducing pathway Inhibitors, activators of the innate immune response, further activators of the innate immune response, and sites Including Cain.

[0241] In one embodiment, the drug delivery composition and device are a hydrogel, an inflammation-inducing pathway This includes inhibitors, activators of the innate immune response, and chemokines.

[0242] In one embodiment, the drug delivery composition and device are a hydrogel, an inflammation-inducing pathway Inhibitors, activators of the innate immune response, further activators of the innate immune response, and chemocrates Includes "in".

[0243] In one embodiment, the drug delivery composition and device are a hydrogel, an inflammation-inducing pathway This includes inhibitors and cytokines.

[0244] In one embodiment, the drug delivery composition and device are a hydrogel, an inflammation-inducing pathway This includes inhibitors and chemokines.

[0245] In one embodiment, the drug delivery composition and device are a hydrogel, an inflammation-inducing pathway This includes inhibitors and activators of adaptive immune responses.

[0246] In one embodiment, the drug delivery composition and device are a hydrogel, an inflammation-inducing pathway This includes inhibitors, activators of the innate immune response, and activators of the adaptive immune response.

[0247] In one embodiment, the drug delivery composition and device are a hydrogel, an inflammation-inducing pathway Inhibitors, activators of the innate immune response, further activators of the innate immune response, and adaptive immune It contains activators of the epidemic response.

[0248] In one embodiment, the drug delivery composition and device are a hydrogel, an inflammation-inducing pathway This includes inhibitors, activators of adaptive immune responses, and further activators of adaptive immune responses.

[0249] In one embodiment, the drug delivery composition and device are a hydrogel, an inflammation-inducing pathway Inhibitors, activators of adaptive immune responses, and two further activators of adaptive immune responses include.

[0250] In one embodiment, the drug delivery composition and device are a hydrogel, an inflammation-inducing pathway Inhibitors, activators of the innate immune response, cytokines, and activators of the adaptive immune response include.

[0251] In one embodiment, the drug delivery composition and device are a hydrogel, an inflammation-inducing pathway Inhibitors, activators of the innate immune response, further activators of the innate immune response, cytokines , and include activators of adaptive immune responses.

[0252] In one embodiment, the drug delivery composition and device are a hydrogel, an inflammation-inducing pathway Inhibitors, activators of the innate immune response, cytokines, activators of the adaptive immune response, and It contains factors that activate further adaptive immune responses.

[0253] In one embodiment, the drug delivery composition and device are a hydrogel, an inflammation-inducing pathway Inhibitors, activators of the innate immune response, further activators of the innate immune response, cytokines This includes activators of adaptive immune responses, and further activators of adaptive immune responses.

[0254] In one embodiment, the drug delivery composition and device are a hydrogel, an inflammation-inducing pathway It includes inhibitors, activators of the innate immune response, chemokines, and activators of the adaptive immune response. nothing.

[0255] In one embodiment, the drug delivery composition and device are a hydrogel, an inflammation-inducing pathway Inhibitors, activators of the innate immune response, further activators of the innate immune response, chemokines, and includes activators of adaptive immune responses.

[0256] In one embodiment, the drug delivery composition and device are a hydrogel, an inflammation-inducing pathway Inhibitors, activators of the innate immune response, chemokines, activators of the adaptive immune response, and It contains various activators of adaptive immune responses.

[0257] In one embodiment, the drug delivery composition and device are a hydrogel, an inflammation-inducing pathway Inhibitors, activators of the innate immune response, further activators of the innate immune response, chemokines, It includes activators of adaptive immune responses, and activators of further adaptive immune responses.

[0258] In one embodiment, the drug delivery composition and device are a hydrogel, an inflammation-inducing pathway This includes inhibitors, cytokines, and activators of adaptive immune responses.

[0259] In one embodiment, the drug delivery composition and device are a hydrogel, an inflammation-inducing pathway Inhibitors, cytokines, activators of adaptive immune responses, and further activation of adaptive immune responses Contains chemical factors.

[0260] In one embodiment, the drug delivery composition and device are a hydrogel, an inflammation-inducing pathway This includes inhibitors, chemokines, and activators of adaptive immune responses.

[0261] In one embodiment, the drug delivery composition and device are a hydrogel, an inflammation-inducing pathway Inhibitors, chemokines, activators of adaptive immune responses, and further activation of adaptive immune responses Includes factors.

[0262] In one embodiment, the drug delivery composition and device are a hydrogel and an anti-IL-1β anti Including the body.

[0263] In one embodiment, the drug delivery composition and device include a hydrogel and an anti-IL-6 antibody. Includes.

[0264] In one embodiment, the drug delivery composition and device are a hydrogel and an anti-IL-6R anti Including the body.

[0265] In one embodiment, the drug delivery composition and device are a hydrogel and p38 mit Inhibition of pro-inflammatory immune responses mediated by the Gen-activated protein kinase (MAPK) pathway. Contains the agent.

[0266] In one embodiment, the drug delivery composition and device include a hydrogel and a p38 MAPK inhibitor. Contains harmful substances.

[0267] In one embodiment, the drug delivery composition and device are a hydrogel and P38 MAPK Contains a p38α / βMAPK inhibitor that binds to ATP and / or allosteric binding sites.

[0268] In one embodiment, the drug delivery composition and device are a hydrogel and rosmapimo Includes "do".

[0269] In one embodiment, the drug delivery composition and device are hydrogel and TGFβR inhibitors. Contains the agent.

[0270] In one embodiment, the drug delivery composition and device include a hydrogel and a CCR2 inhibitor. Includes.

[0271] In one embodiment, the drug delivery composition and device are a hydrogel and CXCR4 inhibitor. Contains the agent.

[0272] In one embodiment, the drug delivery composition and device include a hydrogel, an anti-IL-1β antibody, and includes interferon gene stimulating factor (STING) agonists.

[0273] In one embodiment, the drug delivery composition and device include a hydrogel, an anti-IL-6 antibody, and It also contains interferon gene stimulating factor (STING) agonists.

[0274] In one embodiment, the drug delivery composition and device include a hydrogel, an anti-IL-6R antibody, and includes interferon gene stimulating factor (STING) agonists.

[0275] In one aspect, the drug delivery composition and device include a hydrogel, a TGFβR inhibitor, and includes interferon gene stimulating factor (STING) agonists.

[0276] In one embodiment, the drug delivery composition and device include a hydrogel, a CCR2 inhibitor, and It also contains interferon gene stimulating factor (STING) agonists.

[0277] In one embodiment, the drug delivery composition and device include a hydrogel, a CXCR4 inhibitor, and includes interferon gene stimulating factor (STING) agonists.

[0278] In one embodiment, the drug delivery composition and device are a hydrogel, p38 mitogel. Inhibitors of pro-inflammatory immune responses mediated by the activated protein kinase (MAPK) pathway, and includes TLR7 / 8 agonists.

[0279] In one embodiment, the drug delivery composition and device include a hydrogel and a p38 MAPK inhibitor. , and TLR7 / 8 agonists.

[0280] In one embodiment, the drug delivery composition and device are a hydrogel, P38 MAPK AT p38α / βMAPK inhibitors that bind to P and / or allosteric binding sites, as well as TLR7 / Includes 8 agonists.

[0281] In one embodiment, the drug delivery composition and device include a hydrogel, rosmapimod, and includes TLR7 / 8 agonists.

[0282] In one embodiment, the drug delivery composition and device include a hydrogel, an anti-IL-1β antibody, and includes 2'3'-cGAMP.

[0283] In one embodiment, the drug delivery composition and device include a hydrogel, an anti-IL-6 antibody, and This includes 2'3'-cGAMP.

[0284] In one embodiment, the drug delivery composition and device include a hydrogel, an anti-IL-6R antibody, and includes 2'3'-cGAMP.

[0285] In one embodiment, the drug delivery composition and device include a hydrogel, an anti-IL-1β antibody, and includes 2'3'-c-di-AM(PS)2(Rp,Rp).

[0286] In one embodiment, the drug delivery composition and device include a hydrogel, an anti-IL-6 antibody, and This includes 2'3'-c-ji-AM(PS)2(Rp,Rp).

[0287] In one embodiment, the drug delivery composition and device include a hydrogel, an anti-IL-6R antibody, and includes 2'3'-c-di-AM(PS)2(Rp,Rp).

[0288] In one embodiment, the drug delivery composition and device are a hydrogel, p38 mitogel. Inhibitors of pro-inflammatory immune responses mediated by the activated protein kinase (MAPK) pathway, and includes reciquimod.

[0289] In one embodiment, the drug delivery composition and device include a hydrogel and a p38 MAPK inhibitor. , and reciquimod.

[0290] In one embodiment, the drug delivery composition and device include a hydrogel, ATP of P38 MAPK. and / or p38α / βMAPK inhibitors that bind to allosteric binding sites, and reciquimo Includes "do".

[0291] In one embodiment, the drug delivery composition and device include a hydrogel, rosmapimod, and includes reciquimod.

[0292] In one embodiment, the drug delivery composition and device include a hydrogel and a reximod Includes.

[0293] In one embodiment, the drug delivery composition and device include hyaluronic acid and anti-IL-1β Including the body.

[0294] In one embodiment, the drug delivery composition and device include hyaluronic acid and an anti-IL-6 antibody. Includes.

[0295] In one embodiment, the drug delivery composition and device include hyaluronic acid and anti-IL-6R anti Including the body.

[0296] In one embodiment, the drug delivery composition and device include hyaluronic acid and p38 mit Inhibition of pro-inflammatory immune responses mediated by the Gen-activated protein kinase (MAPK) pathway. Contains the agent.

[0297] In one embodiment, the drug delivery composition and device include hyaluronic acid and p38 MAPK inhibitor. Contains harmful substances.

[0298] In one embodiment, the drug delivery composition and device include hyaluronic acid and P38 MAPK This includes a p38α / βMAPK inhibitor that binds to the ATP and / or allosteric binding site.

[0299] In one embodiment, the drug delivery composition and device include hyaluronic acid and rosmapimo Includes "do".

[0300] In one embodiment, the drug delivery composition and device are hyaluronic acid and TGFβR inhibitors. Contains the agent.

[0301] In one embodiment, the drug delivery composition and device include hyaluronic acid and a CCR2 inhibitor. Includes.

[0302] In one embodiment, the drug delivery composition and device are hyaluronic acid and CXCR4 inhibitors. Contains the agent.

[0303] In one embodiment, the drug delivery composition and device include hyaluronic acid, anti-IL-1β antibody, and includes interferon gene stimulating factor (STING) agonists.

[0304] In one embodiment, the drug delivery composition and device include hyaluronic acid, an anti-IL-6 antibody, and It also contains interferon gene stimulating factor (STING) agonists.

[0305] In one embodiment, the drug delivery composition and device include hyaluronic acid, anti-IL-6R antibody, and includes interferon gene stimulating factor (STING) agonists.

[0306] In one embodiment, the drug delivery composition and device include hyaluronic acid, a TGFβR inhibitor, and includes interferon gene stimulating factor (STING) agonists.

[0307] In one embodiment, the drug delivery composition and device include hyaluronic acid, a CCR2 inhibitor, and It also contains interferon gene stimulating factor (STING) agonists.

[0308] In one embodiment, the drug delivery composition and device include hyaluronic acid, a CXCR4 inhibitor, and includes interferon gene stimulating factor (STING) agonists.

[0309] In one embodiment, the drug delivery composition and device include hyaluronic acid, p38 mitogel. Inhibitors of pro-inflammatory immune responses mediated by the activated protein kinase (MAPK) pathway, and includes TLR7 / 8 agonists.

[0310] In one embodiment, the drug delivery composition and device include hyaluronic acid and a p38 MAPK inhibitor. , and TLR7 / 8 agonists.

[0311] In one embodiment, the drug delivery composition and device include hyaluronic acid, ATP of P38 MAPK. p38α / βMAPK inhibitors that bind to allosteric binding sites, and TLR7 / 8 Includes agonists.

[0312] In one embodiment, the drug delivery composition and device include hyaluronic acid, rosmapimod, and includes TLR7 / 8 agonists.

[0313] In one embodiment, the drug delivery composition and device include hyaluronic acid, anti-IL-1β antibody, and includes 2'3'-cGAMP.

[0314] In one embodiment, the drug delivery composition and device include hyaluronic acid, an anti-IL-6 antibody, and This includes 2'3'-cGAMP.

[0315] In one embodiment, the drug delivery composition and device include hyaluronic acid, anti-IL-6R antibody, and includes 2'3'-cGAMP.

[0316] In one embodiment, the drug delivery composition and device include hyaluronic acid, anti-IL-1β antibody, and includes 2'3'-c-di-AM(PS)2(Rp,Rp).

[0317] In one embodiment, the drug delivery composition and device include hyaluronic acid, an anti-IL-6 antibody, and This includes 2'3'-c-ji-AM(PS)2(Rp,Rp).

[0318] In one embodiment, the drug delivery composition and device include hyaluronic acid, anti-IL-6R antibody, and includes 2'3'-c-di-AM(PS)2(Rp,Rp).

[0319] In one embodiment, the drug delivery composition and device include hyaluronic acid, p38 mitogel. Inhibitors of pro-inflammatory immune responses mediated by the activated protein kinase (MAPK) pathway, and includes reciquimod.

[0320] In one embodiment, the drug delivery composition and device include hyaluronic acid and a p38 MAPK inhibitor. , and reciquimod.

[0321] In one embodiment, the drug delivery composition and device include hyaluronic acid, ATP of P38 MAPK. and / or p38α / βMAPK inhibitors that bind to allosteric binding sites, and reciquimo Includes "do".

[0322] In one embodiment, the drug delivery composition and device include hyaluronic acid, rosmapimod, and includes reciquimod.

[0323] In one embodiment, the drug delivery composition and device include hyaluronic acid and reximod Includes.

[0324] In one embodiment, the drug delivery composition and device are an alginate and an anti-IL-1β anti- Including the body.

[0325] In one embodiment, the drug delivery composition and device include an alginate and an anti-IL-6 antibody. Includes.

[0326] In one embodiment, the drug delivery composition and device are an alginate and an anti-IL-6R anti Including the body.

[0327] In one embodiment, the drug delivery composition and device are alginate and p38 mite Inhibition of pro-inflammatory immune responses mediated by the Gen-activated protein kinase (MAPK) pathway. Contains the agent.

[0328] In one embodiment, the drug delivery composition and device include alginate and p38 MAPK inhibitor. Contains harmful substances.

[0329] In one embodiment, the drug delivery composition and device are alginate and P38 MAPK Contains a p38α / βMAPK inhibitor that binds to ATP and / or allosteric binding sites.

[0330] In one embodiment, the drug delivery composition and device are alginate and rosmapimo Includes "do".

[0331] In one embodiment, the drug delivery composition and device include alginate, anti-IL-1β antibody, and includes interferon gene stimulating factor (STING) agonists.

[0332] In one embodiment, the drug delivery composition and device include alginate, an anti-IL-6 antibody, and It also contains interferon gene stimulating factor (STING) agonists.

[0333] In one embodiment, the drug delivery composition and device include alginate, anti-IL-6R antibody, and includes interferon gene stimulating factor (STING) agonists.

[0334] In one embodiment, the drug delivery composition and device are alginate, p38 mitojel Inhibitors of pro-inflammatory immune responses mediated by the activated protein kinase (MAPK) pathway, and includes TLR7 / 8 agonists.

[0335] In one embodiment, the drug delivery composition and device include alginate, p38 MAPK inhibitor. , and TLR7 / 8 agonists.

[0336] In one embodiment, the drug delivery composition and device include alginate, P38 MAPK, and ATP. p38α / βMAPK inhibitors that bind to allosteric binding sites, and TLR7 / 8 Includes agonists.

[0337] In one embodiment, the drug delivery composition and device include alginate, rosmapimod, and includes TLR7 / 8 agonists.

[0338] In one embodiment, the drug delivery composition and device include alginate, anti-IL-1β antibody, and includes 2'3'-cGAMP.

[0339] In one embodiment, the drug delivery composition and device include alginate, an anti-IL-6 antibody, and This includes 2'3'-cGAMP.

[0340] In one embodiment, the drug delivery composition and device include alginate, anti-IL-6R antibody, and includes 2'3'-cGAMP.

[0341] In one embodiment, the drug delivery composition and device include alginate, anti-IL-1β antibody, and includes 2'3'-c-di-AM(PS)2(Rp,Rp).

[0342] In one embodiment, the drug delivery composition and device include alginate, an anti-IL-6 antibody, and This includes 2'3'-c-ji-AM(PS)2(Rp,Rp).

[0343] In one embodiment, the drug delivery composition and device include alginate, anti-IL-6R antibody, and includes 2'3'-c-di-AM(PS)2(Rp,Rp).

[0344] In one embodiment, the drug delivery composition and device are alginate, p38 mitojel Inhibitors of pro-inflammatory immune responses mediated by the activated protein kinase (MAPK) pathway, and includes reciquimod.

[0345] In one embodiment, the drug delivery composition and device include alginate, p38 MAPK inhibitor. , and reciquimod.

[0346] In one embodiment, the drug delivery composition and device include alginate, P38 MAPK, and ATP. and / or p38α / βMAPK inhibitors that bind to allosteric binding sites, and reciquimo Includes "do".

[0347] In one embodiment, the drug delivery composition and device include alginate, rosmapimod, and includes reciquimod.

[0348] In one embodiment, the drug delivery composition and device include alginate and reximod Includes.

[0349] In one embodiment, the drug delivery composition and device include alginates, COX-2 inhibitors (e.g.) For example, it does not contain celecoxib or anti-PD-1 antibodies.

[0350] In one embodiment, the drug delivery composition and device are 1,3,-bis(2-chloroethyl)-1- It does not contain nitrosourea (BCNU) or ethylene-vinyl acetate copolymer.

[0351] Characterizing drug delivery compositions and devices The biomaterials useful for the drug delivery compositions and devices described herein are , biocompatible. In some embodiments, biomaterials (e.g., hydrogels) are biocompatible. It is biodegradable. The drug delivery compositions and devices are chemically and / or biologically degradable. The composition and device can be broken down under physiological conditions, for example, within the body. Degradation can occur at varying rates, depending on the constituent components and the hydrogel used. For example, the half-life of the composition and the device (50% of the composition is monomer and / or other non-polyphosphate The time it takes to break down into the rimmer-like parts can range from days, weeks, months, or even years. The composition and device may be biologically determined, for example, by enzyme activity or cellular mechanisms. In some cases, for example, through exposure to lysozyme (for example, at relatively low pH Even if it is decomposed (having the properties of) or decomposed by simple hydrolysis It may be done. In some cases, the composition and device may be such that the cells are subjected to Monomers and / Alternatively, they may decompose into other non-polymeric parts. Drug delivery compositions and devices are such However, it is stable in vivo to deliver the drug to the intended target within a favorable timeframe.

[0352] In some respects, less than 90%, less than 80%, less than 70%, less than 60%, less than 50% of the device, 40% or less, 30% or less, 20% or less, 10% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% The following applies to the administration of drug delivery compositions or devices (e.g., 0.5% or less, or 0.1% or less). It persists in vivo 12 months after planting.

[0353] In one aspect, the composition may be 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, or 40%. % or less, 30% or less, 20% or less, 10% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less Below, 0.5% or less, or 0.1% or less, is used for the administration (e.g., implantation) of drug delivery compositions or devices. It remains in vivo six months later.

[0354] In one aspect, the composition may be 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, or 40%. % or less, 30% or less, 20% or less, 10% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less Below, 0.5% or less, or 0.1% or less, is used for the administration (e.g., implantation) of drug delivery compositions or devices. It remains in vivo five months later.

[0355] In some cases, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, 30% or less, 20% or less, 10% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.5% The following, or 0.1% or less, four months after administration (e.g., implantation) of the drug delivery composition or device: It remains in vivo.

[0356] In some cases, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, 30% or less, 20% or less, 10% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.5% The following percentages, or 0.1% or less, three months after administration (e.g., implantation) of the drug delivery composition or device. It remains in vivo.

[0357] In one aspect, the composition may be 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, or 40%. % or less, 30% or less, 20% or less, 10% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less Below, 0.5% or less, or 0.1% or less, is used for the administration (e.g., implantation) of drug delivery compositions or devices. It remains in vivo two months later.

[0358] In one aspect, the composition may be 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, or 40%. % or less, 30% or less, 20% or less, 10% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less Below, 0.5% or less, or 0.1% or less, is used for the administration (e.g., implantation) of drug delivery compositions or devices. It remains in vivo one month later.

[0359] In one aspect, the composition may be 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, or 40%. % or less, 30% or less, 20% or less, 10% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less Below, 0.5% or less, or 0.1% or less, is used for the administration (e.g., implantation) of drug delivery compositions or devices. It remains in vivo one week later.

[0360] In one aspect, the composition may be 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, or 40%. % or less, 30% or less, 20% or less, 10% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less Below, 0.5% or less, or 0.1% or less, is the administration of a drug delivery composition or device (for example) It remains in vivo one day after transplantation.

[0361] The storage modulus of a viscoelastic material measures the stored energy of the elastic portion of the material. The storage modulus can be measured by a rheometer. Measurements were performed at room temperature using a TA Instruments AR-G2 magnetic bearing rheometer. The storage modulus of drug delivery compositions and devices varies based on the composition's components. Ro.

[0362] Generally, thiol-modified hyaluronic acid (e.g., GLYCOSIL®) and thiol The relationship between the storage modulus and concentration of a reactive PEGDA crosslinking agent (e.g., EXTRALINK®). The relationship is linear (excluding the limits of sensitivity). For example, 0.8% GLYCOSIL® The formulation containing 0.2% EXTRALINK® has a storage modulus of approximately 100 Pa and 1.3% GLYC The OSIL® and 2% EXTRALINK® formulation has a storage modulus of approximately 1600 Pa. They will.

[0363] In one embodiment, the drug delivery composition or device described herein is less At least 50 Pa, at least 100 Pa, at least 200 Pa, at least 300 Pa, at least 400 Pa , at least 500 Pa, at least 600 Pa, at least 700 Pa, at least 800 Pa, at 900 Pa, at least 1000 Pa, at least 1100 Pa, at least 1200 Pa, at least 1300 Pa, At least 1400 Pa, at least 1500 Pa, at least 1600 Pa, at least 1700 Pa, and at least Also 1800 Pa, at least 1900 Pa, at least 2000 Pa, at least 2100 Pa, at least 2200 Pa , at least 2300 Pa, at least 2400 Pa, at least 2500 Pa, at least 2600 Pa, less Storage elasticity of 2700 Pa, at least 2800 Pa, at least 2900 Pa, or at least 3000 Pa It has a rate.

[0364] In one embodiment, the drug delivery composition or device described herein is about 50 Pa to approximately 100,000,000 Pa, approximately 50 Pa to approximately 100,000 Pa, approximately 50 Pa to approximately 10,000 Pa, approximately 50 Pa to approximately 3,000 Pa a, about 100Pa to about 3,000Pa, about 100Pa to about 2,000Pa, about 500Pa to about 3,000Pa, about 500Pa to about 2,000P a. Approximately 1,000 Pa to 2,000 Pa, approximately 1,200 Pa to 1,800 Pa, approximately 1,300 Pa to 1,700 Pa, or approximately 1,4 It has a storage modulus of elasticity ranging from 00 Pa to approximately 1,600 Pa.

[0365] In one embodiment, the drug delivery composition or device described herein is about Up to 600 Pa, up to approximately 700 Pa, up to approximately 800 Pa, up to approximately 900 Pa, up to approximately 1,000 Pa, up to approximately 1,100 Pa, Up to approximately 1,200 Pa, up to approximately 1,300 Pa, up to approximately 1,400 Pa, up to approximately 1,500 Pa, up to approximately 1,600 Pa, approximately 1,7 Up to 00 Pa, up to approximately 1,800 Pa, up to approximately 1,900 Pa, up to approximately 2,000 Pa, up to approximately 2,500 Pa, up to approximately 3,000 Pa Up to approximately 5,000 Pa, up to approximately 10,000 Pa, up to approximately 100,000 Pa, up to approximately 1,000,000 Pa, approximately 10,000 It has a storage modulus of elasticity down to 0,000 Pa, or up to approximately 100,000,000 Pa.

[0366] The drug delivery compositions and devices described herein are used under physiological conditions. For example, the body releases one or more therapeutic agents. The release of one or more therapeutic agents is also This depends on the components of the device (e.g., the identity and concentration of the hydrogel). This can occur at various speeds. For example, the release rate of one or more therapeutic agents (the therapeutic agent is no longer composed The time (the time during which an object or device is no longer a part of it) can be a few minutes, a few hours, a few days, a few weeks, or several minutes. This may be on a monthly or multi-year scale. Therapeutic agents work through various mechanisms, for example It may be released by diffusion, chemical activity, enzymatic activity, or cellular mechanisms. Several embodiments In this specification, the drug delivery compositions and devices described herein are preferred It is stable in vivo to deliver the drug to the intended target within an appropriate timeframe.

[0367] In one aspect, less than 90%, less than 80%, less than 70%, and less than 60% of the activating factors of the innate immune system. Below, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, 5% or less, or 1% or less. 4 weeks, 3 weeks, 2 weeks, 10 days, 7 days, 6 weeks after administration (e.g., implantation) of the composition or device. 1 day, 5 days, 4 days, 3 days, 2 days, 1 day, 18 hours, 12 hours, 8 hours, 6 hours, 4 hours, 3 Within a few hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, 15 minutes, or 10 minutes, in vivo It is released.

[0368] In one embodiment, over 99%, over 95%, over 90%, and 80% of the activating factors of the innate immune system. % or more, 70% or more, 60% or more, 50% or more, 40% or more, 30% or more, 20% or more, 10% or more, 5 % or more, or 1% or more, for 1 day or 18 hours after administration (e.g., implantation) of the composition or device. Intervals: 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, 15 It is released in vivo within a minute or 10 minutes.

[0369] In one aspect, any further activators of the innate immune system are less than 90%, less than 80%, or 70%. % or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, 5% or less, Or, less than 1% after 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 It will be released in vivo within a certain time.

[0370] In one embodiment, more than 99%, more than 95%, and 90% of any further innate immune system activators. % or more, 80% or more, 70% or more, 60% or more, 50% or more, 40% or more, 30% or more, 20% or more, 10 % or more, 5% or more, or 1% or more after administration (e.g., implantation) of the composition or device, Days, 18 hours, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, It is released in vivo within 20 minutes, 15 minutes, or 10 minutes.

[0371] In one aspect, less than 90%, less than 80%, less than 70%, and less than 60% of the activators of the adaptive immune system. Below, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, 5% or less, or 1% or less. After administration (e.g., implantation) of the composition or device, for 4 weeks, 3 weeks, 2 weeks, 10 days, and 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 Within a few hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, 15 minutes, or 10 minutes, in vivo It is released.

[0372] In one embodiment, over 99%, over 95%, over 90%, and over 80% of the activating factors of the adaptive immune system Above, 70% or more, 60% or more, 50% or more, 40% or more, 30% or more, 20% or more, 10% or more, 5% or more The above, or 1% or more, for 1 day or 18 hours after administration (e.g., implantation) of the composition or device. 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, 15 minutes or released in vivo within 10 minutes.

[0373] In one aspect, any further adaptive immune system activators of 90%, 80%, or 70% % or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, 5% or less, Or, less than 1% after 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 It will be released in vivo within a certain time.

[0374] In one embodiment, more than 99%, more than 95%, and 90% of any further adaptive immune system activators. % or more, 80% or more, 70% or more, 60% or more, 50% or more, 40% or more, 30% or more, 20% or more, 10 % or more, 5% or more, or 1% or more after administration (e.g., implantation) of the composition or device, Days, 18 hours, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, It is released in vivo within 20 minutes, 15 minutes, or 10 minutes.

[0375] In one aspect, cytokines are reduced to less than 90%, less than 80%, less than 70%, less than 60%, or less than 50%. Below, 40% or less, 30% or less, 20% or less, 10% or less, 5% or less, or 1% or less is the composition or The following intervals are observed after device administration (e.g., implantation): 4 weeks, 3 weeks, 2 weeks, 10 days, 7 days, 6 days, and 5 days. Intervals: 4 days, 3 days, 2 days, 1 day, 18 hours, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours Released in vivo within the interval of 1 hour, 45 minutes, 30 minutes, 20 minutes, 15 minutes, or 10 minutes. ru.

[0376] In one embodiment, over 99%, over 95%, over 90%, over 80%, and over 70% of cytokines Above, 60% or more, 50% or more, 40% or more, 30% or more, 20% or more, 10% or more, 5% or more, or 1 % or more were present at 1 day, 18 hours, 12 hours, and 8 hours after administration (e.g., implantation) of the composition or device. Intervals, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, 15 minutes, or 10 It is released in vivo within minutes.

[0377] Preparation and administration of drug delivery compositions and devices This disclosure includes drug delivery compositions and devices containing therapeutic agents as described herein. To provide a chair. In one embodiment, the therapeutic agent treats a disease (e.g., a proliferative disorder such as cancer). For treatment and / or prevention, in an effective amount in drug delivery compositions and devices Provided. In one embodiment, the effective dose is the therapeutically effective dose of a particular therapeutic agent. In one embodiment In this context, the effective dose is the prophylactic effective dose of a particular therapeutic agent.

[0378] The drug delivery compositions and devices described herein are publicly available in the pharmaceutical field. It can be prepared by any method of knowledge. In one embodiment, such preparation method is Steps include adding all-modified hyaluronic acid to the template; inhibitors of the pro-inflammatory pathway (for example) The step of adding an inhibitor of the pro-inflammatory immune response mediated by the p38 MAPK pathway; Optionally, add an activator of the adaptive immune response to the template; optionally, add a chemokine or Steps include adding cytokines to the template; optionally adding activators of the innate immune response to the template. Steps to add; step to add a crosslinking agent to the mold (e.g., thiol-reactive PE GDA crosslinking agent); and the mixture for at least 10 minutes, at least 15 minutes, at least 20 minutes Between, for at least 25 minutes, at least 30 minutes, at least 35 minutes, at least 40 minutes, less 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 The process includes a step of allowing the mixture to stand for at least 6 hours to allow it to coagulate.

[0379] In one aspect, thiol-modified hyaluronic acid used for the preparation of hydrogels The concentration of glycan acid (e.g., GLYCOSIL®) varies by weight / volume from approximately 1% to approximately 10%. The concentrations are approximately 5% to 1%, 1% to 3%, or 1.5% to 2.5%; and preparation of hydrogels. Thiol-reactive PEGDA crosslinking agents used for this purpose (e.g., EXTRALINK®) The amount varies by weight / volume, ranging from approximately 1% to 20%, 10% to 20%, 5% to 15%, or approximately 1% The concentration is 0% to approximately 15%. In one preferred embodiment, the concentration of thiol-modified hyaluronic acid The saturation level is approximately 2% w / v, and the concentration of the thiol-reactive PEGDA crosslinking agent is approximately 12.5% ​​w / v. In one embodiment, a formulation containing 2% thiol-modified hyaluronic acid and 12.5% ​​is approximately 100 We provide hydrogels with storage modulus ranges from 0 Pa to approximately 2000 Pa.

[0380] For the preparation of standard tissue engineering applications known in the field, thiol-modified The typical concentration of hyaluronic acid (e.g., GLYCOSIL®) is approximately 1% w / v, and thio A typical concentration of a reactive PEGDA crosslinking agent (e.g., EXTRALINK®) is approximately 1% w / It is v. Therefore, 2% w / v thiol-modified hyaluronic acid (e.g., GLYCOSIL ( (Registered trademark)) and 12.5% ​​w / v thiol-reactive PEGDA crosslinking agent (e.g., EXTRALINK (registered trademark)) The use of ) is unexpectedly useful and advantageous in the disclosed drug delivery compositions and devices. To provide biomaterials.

[0381] Those skilled in the art will know how to form a suitable hydrogel (e.g., hyaluronic acid hydrogel). You will understand that other crosslinking agents may be used depending on the concentration. For example, in some embodiments Furthermore, hydrogels (for example, hyaluronic acid hydrogel) contain thiols (for example, EXTRAC L(registered trademark), HYSTEM(registered trademark), methacrylate, hexadecylamide (e.g., HYMOV By adding IS(registered trademark) and / or tyramine (e.g., CORGEL(registered trademark)), It can be crosslinked. In some embodiments, hydrogels (e.g., hyaluronic acid) Divinyl sulfonate hydrogels contain formaldehyde (e.g., HYLAN-A®), divinyl sulfonate. (DVS) (e.g., HYLAN-B(registered trademark)), 1,4-butanediol diglycidyl ether (BDDE) (For example, by RESTYLANE®), glutaraldehyde, and / or genipin, It can be directly crosslinked (for example, Khunmanee et al., "Crosslinking method of hyalu ronic-based hydrogel for biomedical applications” J Tissue Eng. 8: 1-16 (2017) (See reference). In some embodiments, hydrogels (e.g., hyaluronic acid hydrogels) It is crosslinked with divinyl sulfone (DVS) (e.g., HYLAN-B®).

[0382] In one embodiment, the concentration of alginate used for the preparation of hydrogels is heavy Depending on the quantity / volume, the amount of aluminum is approximately 0.5% to 2.5%, 0.75% to 2.0%, or 1.0% to 1.5%. It is a ginate. In one embodiment, 1M chloride is used for the preparation of hydrogels. The amount of the calcium crosslinking agent solution is approximately 5 μL to 25 μL, approximately 10 μL to 20 μL, or approximately 15 μL. In this embodiment, the target payload is mixed with approximately 10 μL to 70 μL of solvent (PBS or DMSO), and 20 μL ~60 μL of solvent (PBS or DMSO), approximately 30 μL to 50 μL of solvent (PBS or DMSO), or approximately 4 It can be loaded in 0 μL of solvent (PBS or DMSO).

[0383] The drug delivery composition and device may further contain at least one excipient. In this embodiment, the excipient is phosphate-buffered saline, tris(hydroxymethyl)aminometh Sodium chloride, potassium chloride, calcium chloride, magnesium sulfate, sodium bicarbonate Lium, sodium phosphate, potassium phosphate, calcium nitrate, glucose, lactose , trehalose, sucrose, or a combination thereof. In one embodiment, The binders are phosphate-buffered saline, tris(hydroxymethyl)aminomethane, and sodium chloride. , or a combination thereof. In one embodiment, the excipient is phosphate-buffered saline. That is the case.

[0384] In one embodiment, the drug delivery composition and device comprises nanoparticles or fine particles. No. Nanoparticles include particles with a size of 1 to 100 nm. Fine particles are 0.1 to 100 μm in size. It contains particles. In one embodiment, the drug delivery composition and device are silica microparticles, Polyethylene microparticles, polystyrene microparticles, polyester microparticles, polyhydrous anhydride microparticles Particles, polycaprolactone microparticles, polycarbonate microparticles, or polyhydroxy It does not contain butyrate microparticles. In one embodiment, the drug delivery composition and device are porous. Does not contain silica microparticles.

[0385] In one embodiment, the drug delivery composition and device comprises one or more organic solvents. In one embodiment, the drug delivery composition and device comprises dimethyl sulfoxide (DMSO). .

[0386] In one embodiment, the drug delivery composition and device are free of organic solvents. In this context, organic solvents are not used in the preparation of the composition or device. In this configuration, the drug delivery composition and device are free of organic solvents. In one embodiment, the drug The drug delivery composition and device are substantially free of organic solvents. In one embodiment, the drug The delivery composition and device are, by weight, less than 10%, less than 5%, less than 4%, less than 3%, and 2%. Less than, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% It contains an organic solvent. In one embodiment, the drug delivery composition and device are by weight, Less than 1000 ppm, less than 500 ppm, less than 400 ppm, less than 300 ppm, less than 200 ppm, less than 100 ppm, less than 50 ppm Full, less than 40 ppm, less than 30 ppm, less than 20 ppm, less than 10 ppm, less than 1 ppm, less than 10 ppb, or 1 ppb Contains less than 1% organic solvent. In one embodiment, the drug delivery composition is dimethyl sulfoxide (D Does not include MSO.

[0387] In one embodiment, the drug delivery composition comprises an organic solvent. It contains cyclodextrin, methanol, ethanol, isopropanol, and ethylene glycoside. It is propyl glycol, or a combination thereof.

[0388] The drug delivery composition and device are available in bulk, as a single unit dose, and / or It can be prepared, packaged and / or sold as multiple single unit doses. "Dosage" refers to a predetermined amount of a specific quantity of a composition or device containing a specific amount of therapeutic agent. The amount of the therapeutic agent is generally equal to the amount of the therapeutic agent that will be administered to the subject, and / or a convenient fraction of such dose, for example, half, one-third, or one-quarter of such dose 1, for example.

[0389] A therapeutic agent, excipient, and / or any further in the composition or device disclosed herein. The relative amount of the component depends on the identity, size, and / or condition of the object being treated. It may exist and change. For example, a composition or device may have a concentration of 0.1% to 99% (w / w), 0.1% to 90% %(w / w), 0.1%~80%(w / w), 0.1%~70%(w / w), 1%~50%(w / w), 10%~80%(w / w), 10 %~90%(w / w), 10%~80%(w / w), 20%~80%(w / w), 30%~80%(w / w), 30%~70%(w / w ), or it may contain 40% to 60% (w / w) of a therapeutic agent.

[0390] Further pharmaceutically acceptable processes may be developed in the manufacture of the provided drug delivery compositions and devices. Excipients may be used. These include inert diluents, dispersants and / or granulators, and granulators. Surfactants and / or emulsifiers, disintegrants, binders, preservatives, buffers, lubricants, and / or It contains oils and fats. Excipients such as cocoa butter and suppository wax, colorants and coatings The guanine agent may also be present in the composition or device.

[0391] Similar diluents include calcium carbonate, sodium carbonate, calcium phosphate, and phosphoric acid. Dicalcium, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose Sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol Inositol, sodium chloride, dried starch, corn starch, powdered sugar, and this These are some examples of combinations.

[0392] Examples of granulating and / or dispersing agents include potato starch, corn starch, and tapioca starch. Oka starch, sodium glycolate starch, clay, alginic acid, guar gum, citrus Tangerine pulp, agar, bentonite, cellulose, and wood products, natural sponges, cations Exchange resin, calcium carbonate, silicate, sodium carbonate, cross-linked poly(vinyl-pyro Lydone (crospovidone), sodium starch carboxymethyl sodium (starch glycolic acid) Sodium, carboxymethylcellulose, cross-linked carboxymethylcellulose Thorium (croscarmellose), methylcellulose, pregelatinized starch Starch (starch 1500), microcrystalline starch, water-insoluble starch, carboxymethylcellulose Sodium, magnesium aluminum silicate (VEEGUM), sodium lauryl sulfate, quaternary ammonium compounds. Examples include ammonium compounds and mixtures thereof.

[0393] Examples of surfactants and / or emulsifiers include natural emulsifiers (e.g., gum arabic). Agar, alginic acid, sodium alginate, tragacanth, chondrux Cholesterol, xanthan gum, pectin, gelatin, egg yolk, casein, lanolin, mites (Telol, wax and lecithin), colloidal clay (e.g., bentonite (aluminum silicate) (Nium) and Veegum (magnesium aluminum silicate), long-chain amino acid derivatives, polymers Amount of alcohol (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol) , triacetin monostearate, ethylene glycol distearate, glyceryl mono (Stearate, propylene glycol monostearate, polyvinyl alcohol) , carbomer (e.g., carboxypolymethylene, polyacrylic acid, acrylic acid polymer) , and carboxyvinyl polymers), carrageenan, cellulose derivatives (e.g., carbo Sodium hydroxymethylcellulose, powdered cellulose, hydroxymethylcellulose, hy Hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose ), sorbitan fatty acid ester (for example, polyoxyethylene sorbitan monolaurate (T Tween (registered trademark) 20), polyoxyethylene sorbitan (Tween (registered trademark) 60), polyoxy Chilensorbitan monolaurate (Tween® 80), sorbitan monopalmitate (Sp an(registered trademark)40), sorbitan monostearate (Span(registered trademark)60), sorbitan tris Thearate (Span® 65), Glyceryl Monolaurate, Sorbitan Monolaurate (Span(registered trademark)80)), polyoxyethylene ester (e.g., polyoxyethylene monosulfide) Thearate (MYRJ 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil Polyoxymethylene stearate, and Solutol), sucrose fatty acid ester, poly Ethylene glycol fatty acid ester (e.g., Cremophor®), polyoxyethylene Poly(vinyl-pylori) (e.g., polyoxyethylene lauryl ether (BRIJ 30)), poly(vinyl-pylori) Don), diethylene glycol monolaurate, oleate triethanolamine, ole Sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate Chill, sodium lauryl sulfate, PLURONIC® F-68 (also known as Poloxamer-188), PLURONI C(registered trademark) F-127 (also known as Poloxamer-407), Cetrimonium bromide, Cetylpyridinium chloride Examples include benzalkonium chloride, sodium doxate, and / or mixtures thereof. It is possible.

[0394] Examples of binders include starch (e.g., cornstarch and starch paste), gelatin. N, sugars (for example, sucrose, glucose, dextrose, dextrin, molasses, Lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., Arabic gums) Agomu, sodium alginate, Irish moss extract, Panwar gum, Gum Ghatti gum, isapol exodermal mucus, carboxymethylcellulose, methyl Cellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose Lurose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate , poly(vinyl-pyrrolidone), magnesium aluminum silicate (VEEGUM), and kala Tualabinogalactan, alginate, polyethylene oxide, polyethylene glyco Lu, inorganic calcium salt, silicic acid, polymethacrylate, wax, water, alcohol, and / Or, a mixture thereof.

[0395] Examples of preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, and aluminum. Examples include chlorine preservatives, acidic preservatives, and other preservatives. In one embodiment, preservation The agent is an antioxidant. In another embodiment, the preservative is a chelating agent.

[0396] Examples of antioxidants include alpha-tocopherol, ascorbic acid, and palmitate. Scorbyl, Butylhydroxyanisole, Butylhydroxytoluene, Monothioglyceride Roll, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate Examples include sodium bisulfite, sodium metabisulfite, and sodium sulfite. It can be done.

[0397] Examples of chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates. Substances (for example, sodium edetate, disodium edetate, trisodium edetate, edetate) (e.g., calcium disodium toxate, dipotassium edetate), citrate and its salts and hydrates (e.g., citric acid monohydrate), fumaric acid and its salts and hydrates, apples Acids and their salts and hydrates, phosphoric acid and its salts and hydrates, and tartaric acid Examples include its salts and hydrates. An example of an antimicrobial preservative is benzalkonium chloride. Um, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetyl chloride Lupyridinium, chlorhexidine, chlorobutanol, chlorocresol, chlorox Lenol, cresol, ethyl alcohol, glycerin, hexetidine, imidourea, f Phenol, phenoxyethanol, phenylethyl alcohol, phenyl nitrate mercury, pro Examples include pyrene glycol and thimerosal.

[0398] Examples of antifungal preservatives include butylparaben, methylparaben, and ethylparaben. Propylparaben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate Examples include sodium ammonium compounds, sodium benzoate, sodium propionate, and sorbic acid.

[0399] Examples of alcoholic preservatives include ethanol, polyethylene glycol, and phenol. Phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, And phenylethyl alcohol are examples.

[0400] Examples of acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, and chlorine. Examples include enoic acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid. It can be done.

[0401] Other preservatives include tocopherol, tocopherol acetate, and tetraoxyme mesylate. (deteroxime mesylate), cetrimide, butylhydroxyanisole (BHA), butylhydro Xytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), lauryl ether Sodium sulfite (SLES), sodium bisulfite, sodium disulfite, potassium sulfite Potassium metabisulfite, Glydant Plus, Phenonip, Methylparaben, Germall 115, Ger Examples include MABEN II, NEOLONE, KATHON, and EUXYL.

[0402] Examples of buffering agents include citrate buffer, acetate buffer, phosphate buffer, and ammonium chloride. Um, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate Calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate Cium, calcium lactate, propionic acid, calcium levulinate, pentanoic acid, dibasic Calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, acetic acid Potassium, potassium chloride, potassium gluconate, potassium mixture, dibasic potassium phosphate Potassium monobasic phosphate, potassium phosphate mixture, sodium acetate, sodium bicarbonate Um, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate M, monobasic sodium phosphate, sodium phosphate mixture, tromethamine, magnesium hydroxide Cium, aluminum hydroxide, alginate, pyrogen-free water, isotonic saline, linguic acid Examples include solutions, ethyl alcohol, and mixtures thereof.

[0403] Examples of lubricants include magnesium stearate, calcium stearate, and stear Phosphate, silica, talc, malt, glyceryl behenate, hydrogenated vegetable oil, polyethylene Recall, sodium benzoate, sodium acetate, sodium chloride, leucine, lauryl Examples include magnesium sulfate, sodium lauryl sulfate, and mixtures thereof.

[0404] Examples of natural oils include almond oil, apricot kernel oil, avocado oil, babassu oil, and bergamot oil. Blackcurrant oil, blackcurrant seed oil, borage oil, cadmium oil, chamomile oil, canola oil, cabbage oil, Lawei oil, carnauba wax oil, castor oil, cinnamon oil, cocoa butter oil, coconut Nut oil, cod liver oil, coffee oil, corn oil, cottonseed oil, emu oil, eucalyptus oil, evening primrose oil Oil, fish oil, linseed oil, geraniol oil, gourd oil, grape seed oil, hazelnut oil, hi Soap oil, isopropyl myristate, jojoba oil, kukui nut oil, lavandin oil, labe Orange oil, lemon oil, Litsea cubeba oil, macadamia nut oil, mallow oil, mango seed oil Meadowfoam seed oil, mink oil, nutmeg oil, olive oil, orange oil, orange lavender Ficus oil, 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, susquam (Sasquana) oil, savory oil, sea buckthorn oil, sesame oil, shea butter oil, silicone Oils, soybean oil, sunflower oil, tea tree oil, thistle oil, camellia oil, vetiver oil, walnut Examples include oils and wheat germ oil. Examples of synthetic fats and oils are not limited to these. However, butyl stearate, caprylic acid triglyceride, capric acid triglyceride, cytophosphate Lomethicone (cyclomethicone), diethyl sebacate, dimethicone 360, iso myristate Propyl, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and These are some possible combinations.

[0405] The drug delivery compositions described herein are primarily suitable for administration to humans. Although directed towards such compositions, those skilled in the art will see that such compositions are generally not suitable for all kinds of animals. It will be understood that the composition is suitable for administration to a variety of animals. Modifications of drug delivery compositions suitable for administration to humans to make them more suitable are well understood. Therefore, a pharmacologist with the usual skills can design and / Alternatively, it may be implemented.

[0406] The drug delivery compositions and devices provided herein are typically used for administration. For ease of use, and for the intended use (e.g., surgical transplantation), the appropriate size (e.g., volume) and It is formulated by weight. However, the total amount of the composition or device of this disclosure (e.g., implanted) The number of devices used will be determined by the attending physician within the bounds of sound medical judgment. It will be understood that specific therapeutic treatments for any particular subject or organism The effective dose level depends on the severity of the disease and disorder being treated; the specific activity used. The activity of the ingredients; the specific composition used; the target age, weight, general health, sex, and diet. ; Time of administration, route of administration, and rate of elimination of the specific active ingredient used; Duration of treatment ; Drugs used in combination with specific active ingredients; and in the field of medicine It will depend on a variety of factors, including well-known similar factors.

[0407] The drug delivery compositions and devices provided herein are administered by surgical implantation. For example, a drug delivery composition or device can be used to deliver a drug to the void of an excised tumor. It can be administered by surgical transplantation in certain quantities. Further examples include drug delivery compositions. Alternatively, the device can be administered by surgical implantation and fixed with a bio-adhesive. In one embodiment, the drug delivery composition or device is provided in the void volume of the excised tumor. It can be fixed using a bio-adhesive.

[0408] In one embodiment, a drug delivery composition or device is used to deliver a tumor excised by surgical implantation. Void volumes of the sore: 100cm, 90cm, 80cm, 70cm, 60cm, 50cm, 40cm, 30cm, 20cm, 10cm, 9cm , 8cm, 7cm, 6cm, 5cm, 4cm, 3cm, 2cm, 1cm, 9mm, 8mm, 7mm, 6mm, 5mm, 4mm, 3mm, 2mm or administered to a site of 1 mm or less. In one embodiment, the void volume of the excised tumor. This refers to the removed organs containing tumors (e.g., lungs, kidneys, pancreas, liver, colon, testes, ovaries, This refers to the void volume of the breast, appendix, and bladder. In one aspect, this refers to the void volume of the resected tumor. The amount is the organ with the tumor (e.g., lungs, kidneys, pancreas, liver, colon, testes, ovaries, breasts, worms) This is the void volume of the resected portion of the bladder (or sphincter).

[0409] In one embodiment, the precursor components of the hydrogel (e.g., hyaluronic acid) and crosslinking The agents are administered separately to the target (for example, at the site of tumor resection), and therefore in vivo A drug delivery composition is formed using a precursor component of a hydrogel (for example) In one embodiment, hydro The gel precursor components (e.g., hyaluronic acid) and crosslinking agents are administered simultaneously. In this embodiment, the precursor components of the hydrogel (e.g., hyaluronic acid) and the crosslinking agent are It is administered as a mixture. In one aspect, administration is by injection.

[0410] In one embodiment, the alginate and crosslinking agent are applied to the target (for example, at the site of tumor resection). They are administered separately and thus form a drug delivery composition in vivo. In this configuration, the alginate and crosslinking agent are administered continuously. In one embodiment, the alginate The arginate and crosslinking agent are administered simultaneously. In one embodiment, the arginate and crosslinking agent are administered simultaneously. The agent is administered as a mixture. In one embodiment, administration is by injection.

[0411] The precise amount of therapeutic agent required to achieve an effective dose depends, for example, on the species and age of the target individual. This depends on the general condition, the severity of side effects or disorders, the identity of the specific drug, etc. Therefore, it will likely vary depending on the subject.

[0412] In one embodiment, the effective amount of the composition or device for administration to a 70 kg adult human is , about 0.0001mg to about 3000mg, about 0.0001mg to about 2000mg, about 0.0001mg to about 1000mg, about 0.001mg to About 1000mg, about 0.01mg to about 1000mg, about 0.1mg to about 1000mg, about 1mg to about 1000mg, about 1mg to about 100mg It may contain approximately 10 mg to 1000 mg, or approximately 100 mg to 1000 mg.

[0413] In one embodiment, the composition or device is intended to target in order to obtain the desired therapeutic effect. Approximately 0.001 mg / kg to 100 mg / kg per kg of body weight per day, approximately 0.01 mg / kg to 50 mg / kg, approximately 0.1 m g / kg~about 40mg / kg, about 0.5mg / kg~about 30mg / kg, about 0.01mg / kg~about 10mg / kg, about 0.1mg / kg~about 10 To deliver either a therapeutic agent present in a composition of mg / kg or approximately 1 mg / kg to approximately 25 mg / kg The dosage level should be sufficient for the purpose of treatment.

[0414] The dose ranges described herein refer to the provided drug delivery compositions and devastations. Providing guidance for the administration of Isu to adults would be understandable. For example. The dosage to be administered to children or adolescents may be determined by a physician or person skilled in the art, and the dosage to be administered to adults It can be lower than this, or it can be the same as this.

[0415] Furthermore, compositions and devices as described herein include one or more further It will be understood that it can be administered in combination with other pharmaceuticals. For example, composition Objects and devices that reduce and / or alter their metabolism, Further medical treatments that inhibit their excretion and / or alter their distribution within the body It can be administered in combination with other medications. Furthermore, any additional treatment used may affect the same disorder. Even if the desired effect is achieved, and / or even if it achieves a different effect Good things will be understood.

[0416] The composition and device may be useful, for example, as a combination therapy, one or more further The pharmaceutical agent can be administered simultaneously with, before, or after the drug. , including therapeutic activators. Pharmaceutical agents also include prophylactic activators. Each further pharmaceutical agent is In the determined dosage and / or time schedule for the pharmaceutical agent, It may be administered. Further pharmaceutical agents may be administered in different doses and / or via different routes of administration. They will be administered separately. Specific combinations for use in a regimen are drugs. Compatibility of the delivery composition with further pharmaceutical agents, and / or desired outcomes to be achieved. Therapeutic and / or preventive effects will be considered. Generally, they are used in combination. Further pharmaceuticals are developed at a level that does not exceed the level at which they are used individually. It is expected to be used. In some forms, it will be used in combination. The level of use will likely be lower than that of individual users.

[0417] Exemplary further pharmaceutical agents include, but are not limited to, antiproliferative agents, anticancer agents, and anti-inflammatory agents. Examples include symptomatic agents, immunosuppressants, and pain relievers. Pharmaceuticals include drug compounds (e.g., (compounds approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR), etc.) Small molecule therapeutic agents, peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins Proteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins Small molecules linked together, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleotides Rheoside, oligonucleotide, antisense oligonucleotide, lipid, hormone, bi Examples include vitamins and cells.

[0418] In one embodiment, the drug delivery composition and device do not contain cells. Furthermore, the drug delivery composition and device do not contain adoptively transferred cells. In some embodiments Furthermore, the drug delivery composition and device do not contain T cells. In one embodiment, further The pharmaceutical agent is not a cell that has been adopted and transferred. In one embodiment, the further pharmaceutical agent is a T cell. It is not a tumor. In one embodiment, the drug delivery composition and device are not tumor antigen-free. In one embodiment, the drug delivery composition and device are used to deliver an ex vivo-loaded tumor anti- Does not include the original.

[0419] In one embodiment, "drug delivery composition" means a composition in liquid form (e.g., viscous This refers to a solution of the drug. In one embodiment, the term "drug delivery device" means a solid in which This refers to a composition (e.g., hydrogel). In one embodiment, the transition from the composition to the device. The resulting material can be physically manipulated and implanted by surgical methods. By having sufficient crosslinking, the storage modulus of elasticity matches the solid form to the extent that it can be achieved. This is possible. Therefore, in its solid form, the drug delivery device is in line with the intent of this disclosure. It may be particularly acceptable for use in the intended application (e.g., surgical transplantation).

[0420] In one embodiment, the drug delivery composition and / or drug delivery device is transported in vivo. It is prepared immediately before implantation (for example, in or near the operating room). In one embodiment, the drug is delivered The drug composition and / or drug delivery device are administered 24 hours, 18 hours, and 12 hours after implantation in vivo. 11 hours, 10 hours, 9 hours, 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour It is prepared in 30 minutes, 20 minutes, 10 minutes, 5 minutes, or within 1 minute.

[0421] In one embodiment, the drug delivery composition and / or drug delivery device is transported in vivo. Prepared prior to planting. In one embodiment, drug delivery composition and / or drug delivery Vice observed the following dates for in vivo transplantation: 31, 28, 21, 14, 7, 6, 5, 4, 3, and 2 days. It is prepared within one day.

[0422] In one embodiment, the drug delivery composition is used for one year in a therapeutic setting. 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 It is prepared within 1 day, 4 days, 3 days, 2 days, or 1 day. In one embodiment, the prepared drug is delivered The composition is then modified by adding a crosslinking agent as described herein. To prepare the drug delivery device, at 31, 28, 21, 14, and 7 days after in vivo implantation, 6th, 5th, 4th, 3rd, 2nd, 1st, 18 hours, 12 hours, 11 hours, 10 hours, 9 hours, 8 hours, 7 hours Intervals of 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 20 minutes, 10 minutes, 5 minutes, or less than 1 minute. Used internally.

[0423] Also included by this disclosure is a kit. The kit provided herein is described herein. The compositions and / or devices described herein, as well as containers (e.g., vials, amplifiers) Bottles, syringes, and / or dispenser packages, or other suitable containers. The kit may include a container. In some embodiments, the kit provided may optionally include the following: Includes pharmaceutical excipients for dilution or suspension of pharmaceutical compositions or compounds described herein. A second container may further be included. In some embodiments, the kit is a drug delivery composition Precursor components for substances and / or drug delivery devices (e.g., hyaluronic acid and A crosslinking agent; or an alginate and a crosslinking agent.

[0424] In one aspect, the kit includes a hydrogel and an inhibitor of the pro-inflammatory pathway (e.g., p38 (Includes inhibitors of pro-inflammatory immune responses mediated by the MAPK pathway.) In one embodiment, The tactic involves hydrogels and inhibitors of pro-inflammatory pathways (e.g., those mediated by the p38 MAPK pathway). It includes inhibitors of pro-inflammatory immune responses and activators of innate immune responses. The kit contains hydrogels and inhibitors of pro-inflammatory pathways (e.g., via the p38 MAPK pathway). The invention includes inhibitors of mediated pro-inflammatory immune responses, and cytokines. In one embodiment The kit contains hydrogels and inhibitors of pro-inflammatory pathways (e.g., those mediated by the p38 MAPK pathway). It includes inhibitors of pro-inflammatory immune responses and activators of adaptive immune responses. In one embodiment, the kit further contains an activator of innate immune function. The kit further contains cytokines. In one embodiment, the kit activates the adaptive immune response. It further contains transformation factors. In one embodiment, the kit enhances the effector function of macrophages. It further includes modifying factors. In one embodiment, the kit activates further adaptive immune responses. The kit further includes factors. In one embodiment, the kit includes oncolytic viruses, radioisotopes, Further includes immunomodulatory chemotherapeutic agents, targeted agents, or combinations thereof. In one embodiment, In one embodiment, the kit comprises any drug delivery composition described herein. In this context, the kit includes any drug delivery device as described herein.

[0425] In one aspect, the kit does not contain chemotherapeutic agents. In another aspect, the kit is It does not contain cytotoxic agents.

[0426] In one embodiment, the kit described herein is for using the kit Further instructions are included. The kits described herein are approved by the U.S. Food and Drug Administration (FDA), etc. It may include information required by regulatory authorities. In one embodiment, the kit may include The information included is prescription information. In one embodiment, the kit and instructions are for the treatment of cancer. Prepare the setup. The kit described herein is one of the kits described herein. The above further pharmaceutical agents may be included as separate compositions.

[0427] Method of treatment and use This disclosure covers cancers in the subject matter (e.g., sarcomas, carcinomas, lymphomas, germ cell tumors or nematodes). For the treatment and / or prevention of proliferative disorders such as cell tumors, as described herein. The present invention provides a method using a drug delivery composition and device. In some embodiments, The compositions and / or devices described in this specification are for the treatment of resectable tumors. It is intended for use in the following manner. In some embodiments, the combination described herein The product and / or device can be used in tissues outside the spleen or lymphatic system, such as the thyroid or stomach. It is intended for use in the treatment of lymphoma present in [location].

[0428] In some embodiments, drug delivery compositions and devices described herein This is useful in treating cancer. In some embodiments, as described herein, The drug delivery compositions and devices described herein delay the onset of cancer symptoms or It is useful in slowing the progression of the disease or in relieving the symptoms. In several aspects In this specification, the drug delivery compositions and devices described herein are for the prevention of cancer. Useful for this purpose. In some embodiments, the drug delivery composition described herein The objects and devices are useful for preventing the regrowth of primary tumors. In some embodiments, In this specification, the drug delivery compositions and devices described herein prevent tumor metastasis. It is useful for the purpose of drug delivery as described herein in some embodiments. The composition and device may be combined with other compounds, drugs, or therapeutic agents for treating cancer. It is administered by hand.

[0429] In some respects, cancer is a solid tumor. In other respects, cancer is a sarcoma, carcinoma. Lymphoma, germ cell tumor, blastoma, or a combination thereof. In addition, tumors include sarcomas, carcinomas, lymphomas, germ cell tumors, blastomas, or combinations thereof. It is a waste.

[0430] In some embodiments, drug delivery compositions and devices described herein This is useful for treating cancers, including but not limited to: acoustic neuroma Adenocarcinoma; Adrenal carcinoma; Anal carcinoma; Angiosarcoma (e.g., lymphangiosarcoma, intra-lymphatic carcinoma) Sarcoma, hemangiosarcoma; appendiceal cancer; benign monoclonal immunoglobulinemia; Biliary tract cancer (e.g., cholangiocarcinoma); cholangiocarcinoma; bladder cancer; bone cancer; breast cancer (e.g., thoracic adenocarcinoma, thoracic Papillary carcinoma, breast cancer, medullary carcinoma of the chest; brain cancer (e.g., meningioma, glioblastoma, glioma (e.g., astrocytoma, oligodendroglioma, medulloblastoma; bronchial cancer; carcinoid tumor; cardiac tumor; child Cervical cancer (e.g., adenocarcinoma of the cervix); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial cancer; ductal carcinoma in situ; ependymoma; epithelium Sarcomas (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcomas); endometrial cancers (e.g., uterine cancer Miyasarcoma; Esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma); Ewing's sarcoma; Ocular cancer (e.g., Intraocular melanoma, retinoblastoma; familial hypereosinophilia; gallbladder cancer; gastric cancer (e.g., adenocarcinoma of the stomach) ); gastrointestinal stromal tumors (GIST); germ cell carcinoma; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer) For example, oral squamous cell carcinoma, throat cancer (for example, laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer); Cancers of the blood system (e.g., lymphoma, primary pulmonary lymphoma, lymphoma of the bronchial lymphoid tissue, spleen) Visceral lymphoma, nodular marginal zone lymphoma, pediatric B-cell non-Hodgkin lymphoma; hemangioblastoma; histiocyte saturation Myofibroblastic disease; hypopharyngeal cancer; inflammatory myofibroblastic tumor; immune cell amyloidosis; kidney cancer (for example) , nephroblastoma, also known as Wilms' tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular carcinoma (HCC), malignant hepatocellular carcinoma) lung cancer (e.g., bronchogenic lung cancer, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), Adenocarcinoma; leiomyosarcoma (LMS); melanoma; linea nigra carcinoma; multiple endocrine neoplasia syndrome; myocarcinoma; mesothelioma Nasopharyngeal carcinoma; neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or 2, schwannoma) Diseases); neuroendocrine carcinomas (e.g., pancreatic gastrointestinal neuroendocrine tumors (GEP-NETs), carcinoid tumors); bone Sarcoma (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, embryonous ovarian carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma ; Pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), islet cell tumor); parathyroid cancer Papillary adenocarcinoma; Penile cancer (e.g., Paget's disease of the penis and scrotum); Pharyngeal cancer; Pineal gland tumor; Pituitary cancer; pleuropulmonary blastoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes Group; carcinoma in situ; prostate cancer (e.g., adenocarcinoma of the prostate); rectal cancer; rhabdomyosarcoma; retinoblastoma Salivary gland carcinoma; Skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthocytoma (KA), melanoma, basal cell carcinoma Cancer (BCC); cancer of the small intestine (e.g., appendiceal cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH)); Liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma; sebaceous gland carcinoma; stomach Cancer; small intestine cancer; sweat gland cancer; synovial tumor; testicular cancer (e.g., seminoma, embryonal testicular cancer); thymic cancer; Thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma); urethral cancer; uterine cancer Cancer; vaginal cancer; vulvar cancer (e.g., Paget's disease of the vulva), or any combination thereof.

[0431] In one sense, cancer is breast cancer. In another sense, cancer is skin cancer. In one sense, cancer is melanoma. In another sense, cancer is lung cancer. In one aspect, the cancer is kidney cancer. In another aspect, the cancer is liver cancer. In one embodiment, the cancer is pancreatic cancer. In another embodiment, the cancer is colorectal cancer. In one sense, cancer is bladder cancer. In another sense, cancer is lymphoma. In one sense, cancer is prostate cancer. In one sense, cancer is thyroid cancer. That is the case.

[0432] In some embodiments, drug delivery compositions and devices described herein It is useful for treating the following: adenocarcinoma, adrenal carcinoma, anal carcinoma, angiosarcoma, appendiceal carcinoma, bile duct Cancer, bladder cancer, bone cancer, brain cancer, breast cancer, bronchial cancer, carcinoid tumors, cardiac tumors, cervical cancer, chorionic villi Hair cancer, chordoma, colorectal cancer, connective tissue cancer, craniopharyngioma, ductal carcinoma in situ, episarcoma, uterine cancer Endometrial cancer, ependymoma, epithelial carcinoma, esophageal cancer, Ewing's sarcoma, ocular cancer, familial hypereosinophilia, gallbladder Cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell carcinoma, head and neck cancer, hematological cancers Igloblastoma, histiocytic proliferative disorder, Hodgkin lymphoma, hypopharyngeal carcinoma, inflammatory myofibroblastic tumor, carcinoma in situ Neoplasms, immune cell amyloidosis, Kaposi's sarcoma, kidney cancer, liver cancer, lung cancer, leiomyosarcoma (L MS, melanoma, linean carcinoma, multiple endocrine neoplasia syndrome, myocarcinoma, mesothelioma, myeloproliferative disorder (MPD) Nasopharyngeal carcinoma, neuroblastoma, neurofibroma, neuroendocrine carcinoma, non-Hodgkin lymphoma, osteosarcoma, ovarian cancer Cancer, pancreatic cancer, paraneoplastic syndrome, parathyroid cancer, papillary carcinoma, penile cancer, pharyngeal cancer, pheochromocytoma, Pineal gland tumor, pituitary cancer, pleuroblastoma, primitive neuroectodermal tumor (PNT), plasma cell neoplasia, Prostate cancer, rectal cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sebaceous gland cancer, skin cancer, small intestine cancer Small intestine cancer, soft tissue sarcoma, stomach cancer, sweat gland cancer, synovial tumor, testicular cancer, thymic cancer, thyroid cancer, urethral cancer Uterine cancer, vaginal cancer, vascular cancer, vulvar cancer, or a combination thereof.

[0433] In some embodiments, drug delivery compositions and devices described herein It is useful in treating and / or preventing solid tumors and metastases.

[0434] For example, in some embodiments, the method is a drug delivery composition as described herein. Objects or devices (e.g., hydrogel biomaterials and inhibitors of the p38 MAPK pathway) This includes administering the drug to a target site that has recently undergone tumor resection. In this configuration, the target site is the tumor resection site. In some embodiments, the target site is the tumor resection site. These are Tinel's lymph nodes. In some embodiments, the target site is the inflow area lymph node. In some embodiments, the target site is used for cancer treatment, such as chemotherapy or radiation therapy. This is the site where cancer cells were previously treated or killed.

[0435] In some embodiments, a drug delivery composition (e.g., hydrogel) is administered to a target site. The biomaterial (containing inhibitors of the p38 MAPK pathway) is a pre-formed gel, and This can be administered to the target site by transplantation. In some embodiments, the target site Drug delivery compositions administered to (e.g., hydrogel precursor components and p38 MAPK) Those containing inhibitors of the pathway are in an injectable format (e.g., liquid). In some aspects, the administrations described herein interact in situ with It reacts to form a gel composition as described herein, one or more biological The process includes administering a precursor component of a material (e.g., hydrogel); in some such embodiments, the odor And such interaction or reaction includes crosslinking, which in some aspects In some cases, this can occur spontaneously, and in some embodiments, the application of an agent (e.g., a catalyst and / or if (or reactants) and / or conditions (e.g., heat, pH, pressure, or specific wavelength) It can be caused by one or more of the following: electromagnetic radiation, etc. Biomaterials (e.g., hydrogels) contain thiols (e.g., EXTRACEL®, HYSTE). M(registered trademark), methacrylate, hexadecylamide (e.g., HYMOVIS(registered trademark)), By adding and / or tyramine (e.g., CORGEL®), crosslinking can be achieved. This is possible. In some embodiments, the biomaterial (e.g., hydrogel) is formaldehyde Dehyde (e.g., HYLAN-A(registered trademark)), Divinylsulfone (DVS) (e.g., HYLAN-B(registered trademark)) (Standard), 1,4-butanediol diglycidyl ether (BDDE) (e.g., RESTYLANE®) It can be directly crosslinked by glutaraldehyde and / or genipine. For example, Khunmanee et al., "Crosslinking method of hyaluronic-based hydrogel for biom See "edical applications," J Tissue Eng. 8: 1-16 (2017). In some aspects Biomaterials (e.g., hydrogels) contain divinyl sulfone (DVS) (e.g., HYLAN-B (registered trademark) It will be bridged by the marker.

[0436] In one embodiment, the method described herein applies to the subject. To deliver an effective amount of the drug delivery composition or device described herein (for example, a biomaterial) (by administration of a gel or a set of its precursors as described herein) Includes. In one embodiment, the methods described herein apply to the subject. To surgically implant an effective amount of the drug delivery composition or device described herein. In one embodiment, the method described herein is used after surgical resection of a tumor. , further comprising implanting a drug delivery composition or device. In one embodiment, the present invention The method described in the details involves delivering a drug delivery composition or device at the site of tumor resection. The method described herein further includes transplanting. In one embodiment, the method described herein , implanting a drug delivery composition or device in the void volume of the excised tumor This further includes: In one embodiment, the method described herein is a tumor resection surgical technique. During surgery, the drug delivery composition or device may be implanted at the tumor resection site. It is included in.

[0437] In one embodiment, the method described herein is based on the weight of the excised tumor. 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more After removal of 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more, This includes administering (e.g., implanting) a drug delivery composition or device. In this specification, the method described herein is based on the volume of the excised tumor, and is 50% or more. 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more After removal of 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more, the drug delivery group This includes administering (e.g., implanting) a substance or device.

[0438] In one embodiment, the method described herein involves delivering a drug to a site adjacent to a tumor. This does not involve administering (e.g., implanting) the composition or device. Furthermore, the method described herein allows for the delivery of a drug adjacent to the tumor without the need for tumor resection. This does not involve administering (e.g., implanting) the composition or device.

[0439] In one embodiment, the drug delivery compositions and devices described herein are... It is administered in combination with one or more additional therapeutic agents as described in the specification. In this context, further treatment options include anticancer drugs.

[0440] In one aspect, the subject being treated is a mammal. In one aspect, the subject The subject is human. In one aspect, the subject received neoadjuvant (preoperative) chemotherapy. The subjects are human patients. In one embodiment, the subjects are human beings who have received neoadjuvant radiotherapy. The patient. In one aspect, the subject receives neoadjuvant chemotherapy and radiotherapy. These are human patients who received the treatment. In one aspect, the subjects are those who received neoadjuvant molecular targeted therapy. It is a human patient. In one embodiment, the subject is immune checkpoint blockade (for example, Humans who have received neoadjuvant immunotherapy including anti-CTLA-4, anti-PD-1, and / or anti-PD-L1. The patient. In one aspect, the subject is immune checkpoint blockade (e.g., anti-CTLA-4). Human patients who have not received neoadjuvant immunotherapy including anti-PD-1 and / or anti-PD-L1) In one aspect, the subject is a person whose tumor is objectively resistant to neoadjuvant therapy. Not responding to the target (Response Evaluation Criteria in Solid Tumors) rs:RECIST or immune-related response criteria (irRC) (As more precisely defined) a human patient (e.g., a stable disease, a progressive disease). The subjects are those whose target lesions are objectively responding to neoadjuvant therapy. For example, partial response, complete response) in human patients. Non-target lesions are incomplete responses, stable diseases. They may be suffering from or exhibiting a progressive disease. In one embodiment, the subject is an adjuvant (surgery). (Later) As a standard of treatment in the setting, the people who would be eligible to receive immunotherapy The patient is a dog, cat, cow, pig, sheep or goat. Which domesticated animal is it? In one embodiment, the subject is a companion animal such as a dog or cat. In one embodiment, the subject is a domesticated animal such as a cattle, pig, horse, sheep, or goat. In one embodiment, the subject is an animal in a zoo. In another embodiment, the subject is a goat. These are research animals such as dentarians, pigs, dogs, or non-human primates. In one embodiment, the subject is non-human transgenic mice or transgenic pigs, etc. Nick is an animal.

[0441] example The following examples are provided so that the invention described herein may be better understood. These examples are for illustrative purposes only and do not apply in any way to the present invention. It should be understood that this should not be interpreted as being restrictive.

[0442] Example 1. Preparation and use of exemplary drug delivery compositions To prepare hydrogels according to some embodiments described herein, Bridgeable hyaluronic acid (e.g., thiol-modified hyaluronic acid such as GLYCOSIL® hyaluronic acid) Hyaluronic acid (and other chemical crosslinking agents such as polyethylene diacrylate) Reactive crosslinking agents, such as EXTRALINK® polyethylene glycol diacrylate. A hydrogel was formed by combining a crosslinking agent. The hydrogel was formed by allowing the reagent to stand for at least one hour. The internal modulus was measured using a rheometer. These results are summarized in Table 1. Table 1. [Table 1]

[0443] The hydrogel for Figure 1 is prepared according to the method described for hydrogel 1 in Table 1. This was prepared. 120 μL of hyaluronic acid solution (2.0% w / v GLYCOSIL) was pipetted into the mold. I administered 1 mg of a p38 MAPK inhibitor (e.g., rosmapimod (Selleckchem)) in 10 μL of DMSO. It was dissolved in the mixture, and this solution was added to the hyaluronic acid solution in the mold. The payload was homogeneous. After mixing to create the fabric, add 30 μL of PEG-diacrylate crosslinking agent solution (12.5% ​​w / v E). XTRALINK was pipetteed into the mold. The crosslinked hydrogel was then subjected to several minutes of processing. During this time, it solidified in the mold. In female BALB / cJ mice, it occurred in the fourth mammary fat pad. 4T1-Luc2 breast cancer cells were inoculated into the cells. Ten days after tumor inoculation, the tumor (approximately 100 mm) 3 ) excised And, a hydrogel loaded with a p38 MAPK inhibitor (e.g., rosmapimod) (e.g., cross-linked A hyaluronic acid hydrogel was placed in the tumor resection site. An empty hydrogel was then placed in the tumor resection site. It was used as a negative control. The benefit of extended survival due to prolonged local release of p38 inhibitors was observed. (Figure 1).

[0444] The hydrogel for Figure 2 was prepared according to the method described for hydrogel 1 in Table 1. This was prepared. 120 μL of hyaluronic acid solution (2.0% w / v GLYCOSIL) was pipetted into the mold. The mixture was mixed with 500 μg (40 μL) of anti-IL-1β antibody (e.g., clone B122 (BioXCell)) in the template. It was added to the hyaluronic acid solution. After mixing to create a uniform distribution of the payload, 30 μL of PEG-diacrylate crosslinking agent solution (12.5% ​​w / v EXTRALINK) was piped into the mold. The cross-linked hydrogel solidified in the mold over a period of several minutes. In BALB / cJ mice, 4T1-Luc2 mammary cancer cells were orthotopically seeded in their fourth mammary fat pad. Ten days after tumor inoculation, the tumor (approximately 100 mm) 3 ) is excised, and anti-IL-1β antibody (for example, ) Hydrogel loaded with Loan B122 (e.g., cross-linked hyaluronic acid hydrogel) The hydrogel was placed in the tumor resection site. An empty hydrogel was used as a negative control. Anti-IL-1β The benefit of extended survival was observed due to the prolonged local release of antibodies (Figure 2).

[0445] The hydrogel for Figure 3 was prepared according to the method described for hydrogel 1 in Table 1. This was prepared. 120 μL of hyaluronic acid solution (2.0% w / v GLYCOSIL) was pipetted into the mold. The following was done: 500 μg (40 μL) of anti-IL-6 antibody (e.g., clone MP5-20F3 (BioXCell)) was used as a template. It was added to the hyaluronic acid solution inside. After mixing to create a uniform distribution of the payload, Then, 30 μL of PEG-diacrylate crosslinking agent solution (12.5% ​​w / v EXTRALINK) was piped into the mold. The cross-linked hydrogel solidified in the mold over a period of several minutes. In BALB / cJ mice, 4T1-Luc2 mammary cancer cells were orthotopically seeded in their fourth mammary fat pad. Ten days after tumor inoculation, the tumor (approximately 100 mm) 3 ) is excised, and an anti-IL-6 antibody (e.g., clo) is used. Hydrogels loaded with (e.g., cross-linked hyaluronic acid hydrogels) (e.g., MP5-20F3) The ) was placed in the tumor resection site. An empty hydrogel was used as a negative control. Anti-IL-6 The benefit of extended survival was observed due to the prolonged local release of antibodies (Figure 3).

[0446] Equivalents and range In the scope of the claim, articles such as "a," "an," and "the" are reversed from the context. Unless otherwise indicated or made clear, it can mean one or more. A claim or statement containing "or" between one or more members of a group is not valid in context. Unless it is shown to be the opposite or otherwise clear, the members of the group Whether one, more than one, or all of them are present in a given product or process. , if used in this, or otherwise related thereto, it is considered to be satisfied This invention allows exactly one member of a group to produce a given product or process. A state that exists in, is used in, or is otherwise related to Seth. This includes. The present invention involves more than one or all of the group, and a given product or is present in the process, used in it, or otherwise related thereto Includes a certain aspect.

[0447] Furthermore, the present invention may include one or more limitations, elements, or clauses from one or more of the listed claims. , and descriptive terms are introduced in other claims, all variations, combinations This includes reordering. For example, any claim dependent on another claim is the same as the basic claim. Modify to include one or more limitations found in any other claim dependent on this. This is possible. If the elements exist as a list, for example in the form of a Markush group, Each subgroup of the elements is also revealed, and any element can be removed from the group. Generally, the present invention or aspects of the present invention include certain elements and / or features. When referred to as such, certain aspects or aspects of the present invention include such elements and / or It should be understood that it consists of features, or that it will become the essence from them. The aim is simplification. Furthermore, those embodiments are not specifically described in this specification. The terms "comprising" and "containing" mean open. Note that this is intended to allow for the inclusion of further elements or steps. The scope is indicated. If applicable, the endpoint is included. Furthermore, as can be seen from the context and the understanding of those skilled in the art, Unless otherwise clearly stated, values ​​expressed as a range may vary in various aspects of the present invention. Any specific value or subrange described in this way, unless the context clearly indicates otherwise. Therefore, it is conceivable that the range could extend down to one-tenth of the lower limit unit.

[0448] This application is based on various issued patents, published patent applications, articles in academic journals, and other publications. The following references are cited and all of them are incorporated herein by reference. In the event of any conflict between any of the references and this specification, this specification shall prevail. In addition, any particular aspect of the present invention that falls under the prior art is claimed. It is explicitly excluded from any one or more of the items. Such a form is known to those skilled in the art. Therefore, they are considered to be excluded unless explicitly stated herein. Even if present, it can be excluded. Any particular aspect of the present invention can be selected from any claim. For reasons of intent, it can be excluded regardless of whether or not it relates to the existence of prior art. ru.

[0449] Those skilled in the art will recognize many equivalents to the specific embodiments described herein. Alternatively, this could be confirmed using only conventional experiments. The scope of the embodiments of the present invention described herein is intended to be limited to the above description. There is none, and it is as described in the attached claims. A person skilled in the art will find the following claims to Without departing from the spirit or scope of the invention as defined in this description, You will understand that a variety of changes and modifications can be made to it.

[0450] The full content of International Patent Publication No. WO 2018 / 045058 (e.g., composition, device, method of preparation, The method of use and the kit) are provided herein for the purposes described herein. It is used as reference.

Claims

1. Biomaterials and p38 mitogen activity in tumor resection sites of cancer patients This includes inhibitors of pro-inflammatory immune responses mediated by the sexual protein kinase (MAPK) pathway. Intraoperative administration of the composition A method that includes the following steps.

2. The biomaterial is characterized by a storage modulus of approximately 500 Pa to approximately 50,000 Pa, as described in claim 1. The method.

3. The method according to claim 1, wherein the administration step does not include adoptive transfer of T cells to a target.

4. The method according to claim 1, wherein the administration step does not involve administering a tumor antigen to a target.

5. The method according to claim 1, wherein the administration step does not involve administering fine particles to a target.

6. The method according to claim 1, wherein the biomaterial is a hydrogel or comprises a hydrogel.

7. The method according to claim 6, wherein the biomaterial is hyaluronic acid or contains hyaluronic acid.

8. The biomaterial is cross-linked hyaluronic acid or contains the same, according to claim 7. method.

9. Whether the biomaterial is hyaluronic acid crosslinked with polyethylene glycol crosslinking agent, The method according to claim 8, which includes the same.

10. The inhibitor is a p38 MAPK inhibitor that binds to the ATP and / or allosteric binding site of p38 MAPK. The method according to claim 1, wherein the agent is a harmful agent or contains the same.

11. The inhibitor binds to the ATP and / or allosteric binding site of p38 MAPK. The method according to claim 1, comprising a PK inhibitor or a PK inhibitor.

12. The p38α / βMAPK inhibitor is rosmapimod or comprises the same, according to claim 11. method.

13. The method according to claim 1, wherein the composition further comprises an activator of innate immunity.

14. The activator of innate immunity is the interferon gene-stimulating factor (STING) agonist. or the method according to claim 13, including the same.

15. Innate immune activators target Toll-like receptor (TLR) 7 and / or TLR8 ("TLR7 / 8") agonists. The method according to claim 13, which is a strike or includes the same.

16. The composition modulates T cells, natural killer (NK) cells, monocytes, and / or dendritic cells. The method according to claim 1, further comprising adaptive immune activators and / or cytokines. 。

17. The composition contains cytokines that regulate T cells, NK cells, monocytes, and / or dendritic cells. It contains; and cytokines, including IL-15 superagonist, IFN-α, IFN-β, IFN-γ The method according to claim 1, selected from, and combinations thereof.

18. The method according to claim 1, wherein the composition further comprises a COX inhibitor.

19. The method according to claim 1, wherein the composition further comprises a COX-2 inhibitor.

20. The method according to claim 1. Biomaterials form a matrix or depot, and inhibitors, It is found in biomaterials.

21. The method according to claim 20, wherein the inhibitor is released by diffusion through a biomaterial.

22. The method according to claim 1, wherein the biomaterial is biodegradable in vivo.

23. By transplanting the biomaterial into the mammary fat body of a mouse, When tested in vivo, less than 10% of the biomaterial remains in vivo 4 months after transplantation. The method according to claim 1, characterized in that

24. The biomaterial is placed in PBS (pH 7.4) along with the composition containing the biomaterial and rosmapimod. When tested in vitro, less than 100% of rosmapimods are viable within 3 hours. The method according to claim 1, characterized in that it is released from the material.

25. The biomaterial is used in a composition containing the biomaterial and rosmapimod in the mammary gland fat tissue of mice. When tested in vivo by transplantation, 50% of rosmapimod The method according to claim 1, characterized in that the following is released in vivo 8 hours after transplantation.

26. When the biomaterial is evaluated 24 hours after administration, and the inhibitor is administered in solution. Compared to what is observed, there are more inhibitors present at the tumor resection site. The method according to claim 1, characterized by extending the release of the inhibitor.

27. The method according to claim 1, wherein the administration is by transplantation.

28. The method according to claim 1, wherein the administration is by injection.

29. The administration involves injecting one or more precursor components of a biomaterial into the tumor resection site. The method according to claim 28, comprising enabling the formation of a biomaterial in a given location.

30. The tumor resection site is characterized by the absence of residual tumor antigens visible to the naked eye, as described in claim 1. Method of loading.

31. The method according to claim 1, wherein the cancer is metastatic cancer.

32. Further steps include monitoring at least one metastatic site in the target after administration. The method according to claim 31, including the method described in claim 31.

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