Microsphere-based drug delivery platform for immunotherapy drug delivery

Abstract

This disclosure relates to biodegradable polymer microspheres comprising a biodegradable polymer and an immunotherapy agent selected from poly-ADP-ribose polymerase enzyme inhibitors (PARP inhibitors) and / or Toll-like receptor (TLR) agonists, wherein the biodegradable polymer microspheres are (a) released from the biodegradable polymer microspheres into a PBS Tween20 (0.05%) solution at 37°C at some point between 3 and 14 days; (b) released from the biodegradable polymer microspheres into a PBS Tween20 (0.05%) solution at 37°C at some point between 3 and 14 days; or (c) both of (a) and (b). Other aspects of this disclosure relate to methods of using such microparticles and kits containing such microparticles.

Description

Background Art

[0001] Immunotherapy has suddenly become the standard treatment for many cancer indications. However, only a small minority of patients respond to this treatment method. In recent years, the focus has shifted to the development of more potent combination therapies and more potent immunomodulatory agents. Many of these next-generation immunotherapies are known to induce a stable anti-tumor immune response. However, the systemic delivery of these immunotherapeutic agents is hampered by strong off-target toxicity. Therefore, there is a need for a drug delivery system that can deliver immunotherapeutic agents to the target tumor in a targeted and controlled manner, thereby improving efficacy while reducing or eliminating off-target toxicity.

Summary of the Invention

[0002] In some aspects, the present disclosure relates to biodegradable polymer microspheres comprising a biodegradable polymer and an immunotherapeutic agent selected from an inhibitor of poly ADP ribose polymerase enzyme (PARP inhibitor) and / or a Toll-like receptor (TLR) agonist, wherein 50% of the total amount of the immunotherapeutic agent in the biodegradable polymer microspheres is released from the biodegradable polymer microspheres into a PBS Tween20 (0.05%) solution at 37°C at a certain point within 3 days to 14 days.

[0003] In some aspects that can be used in combination with the above aspects, the present disclosure relates to biodegradable polymer microspheres comprising a biodegradable polymer and an immunotherapeutic agent selected from an inhibitor of poly ADP ribose polymerase enzyme (PARP inhibitor) and / or a Toll-like receptor (TLR) agonist, wherein 1 mg / g - dry weight microspheres to 100 mg / g - dry weight microspheres are released from the biodegradable polymer microspheres into a PBS Tween2 (0.05%) solution at 37°C at a certain point within 3 days to :14 days.

[0004] In some embodiments that can be used in combination with the above embodiments, the immunotherapy agent is dispersed throughout the particles in the form of nanoparticles having a size of 100 nm to 2000 nm.

[0005] In some embodiments that may be used in combination with the above-described aspects and embodiments, the biodegradable polymer microspheres contain 3% to 10% by weight of the immunotherapeutic agent based on the dry weight of the biodegradable polymer microspheres.

[0006] In some embodiments that can be used in combination with the above-described aspects and embodiments, the biodegradable polymer microspheres have a diameter of 30 to 200 μm. In some embodiments that may be used in combination with the above-described aspects and embodiments, the immunotherapy agent is released by bulk erosion and hydrolysis.

[0007] In some embodiments that can be used in combination with the above-described aspects and embodiments, the biodegradable polymer is a biodegradable polyester. In some embodiments that may be used in combination with the above embodiments, the biodegradable polymer consists of or includes a (lactic acid-glycolic acid) copolymer (PLGA). In some of these embodiments, the ratio of lactic acid units to glycolic acid units in the PLGA is 60:40 to 40:60, typically 50:50. In some of these embodiments, the PLGA includes an acid-terminated PLGA, or the PLGA includes a combination of an acid-terminated PLGA and an ester-terminated PLGA.

[0008] In some embodiments that may be used in combination with the above-described aspects and embodiments, the biodegradable polymer microspheres further include a pharmaceutical excipient selected from the group consisting of preservatives, tension modifiers, viscosity modifiers, pH modifiers, contrast agents, surfactants, and / or sugars or sugar alcohols.

[0009] In some embodiments that can be used in combination with the above embodiments and models, the biodegradable polymer microspheres are provided in a dry form. In some embodiments that can be used in combination with the above aspects and embodiments, the biodegradable polymer microspheres are provided in an aqueous liquid.

[0010] In some embodiments, the biodegradable polymer microspheres may be used in combination with the above embodiments and configurations, and the biodegradable polymer microspheres may be provided in vials or syringes. In some embodiments, the Disclosure relates to (a) biodegradable polymer microspheres according to the above embodiments and models, and (b) a kit comprising any one, any two, any three, any four, any five, or all of the following items: syringe barrels, vials, needles, catheters, guidewires, or injectable liquids.

[0011] In some embodiments, the disclosure relates to a method for treating a patient having a solid tumor, and includes delivering biodegradable polymer microspheres according to the above embodiments and models to the solid tumor.

[0012] In some embodiments, the biodegradable polymer microspheres are delivered by direct injection into the tumor. In some embodiments, the biodegradable polymer microspheres are delivered via one or more blood vessels that supply nutrients to at least a portion of the tumor, and at least a portion of the biodegradable polymer microspheres remains within the blood vessels and causes an embolism.

[0013] In some embodiments that may be used in combination with the above aspects and embodiments, the method further includes treating the solid tumor with radiotherapy. These and other aspects, embodiments and the advantages of the present disclosure will become immediately apparent to those skilled in the art upon reading the following detailed description and claims. [Brief explanation of the drawing]

[0014] [Figure 1] Figure 1 is a micrograph of a biodegradable polymer microsphere manufactured according to one embodiment of the present disclosure. [Figure 2] Figure 2 is a graph showing the kinetic drug release from imiquimod-containing biodegradable polymer microspheres and olaparib-containing biodegradable polymer microspheres to PBS Tween at 37°C according to embodiments of the present disclosure. [Modes for carrying out the invention]

[0015] In various embodiments, this disclosure relates to biodegradable polymer microspheres filled with an immunotherapeutic agent of interest. These biodegradable polymer microspheres are useful for delivering the immunotherapeutic agent to a solid tumor, for example, by direct injection or as an embolizer delivered to the tumor via one or more nutrient vessels. This approach enables controlled and targeted delivery of potent immunotherapeutic agents, thereby improving efficacy at the target site while reducing off-site toxicity.

[0016] In some embodiments, this disclosure relates to biodegradable polymer microspheres comprising a biodegradable polymer and an immunotherapeutic agent, wherein 50% of the total amount of the immunotherapeutic agent in the biodegradable polymer microspheres is released from the biodegradable polymer microspheres into a PBS Tween20 (0.05%) solution at 37°C at some point between 3 and 14 days. In some embodiments, less than 50%, less than 40%, less than 30%, or less than 25% of the immunotherapeutic agent is released on day 3 and / or more than 50%, more than 60%, more than 70%, or more than 80% of the immunotherapeutic agent is released on day 14.

[0017] In some embodiments, this disclosure relates to biodegradable polymer microspheres comprising a biodegradable polymer and an immunotherapeutic agent, wherein 1 mg to 100 mg of the immunotherapeutic agent per gram of dry weight of the microsphere (for example, any range of immunotherapeutic agent from 1 mg to 2 mg to 5 mg to 100 mg per gram of dry weight of the microsphere) is released from the biodegradable polymer microspheres into a PBS Tween20 (0.05%) solution at 37°C at some point between 3 and 14 days.

[0018] In some embodiments, the immunotherapeutic agents used in the present disclosure include poly(ADP-ribose) polymerase (PARP) inhibitors and / or Toll-like receptor (TLR) agonists.

[0019] Examples of PARP inhibitors include olaparib (AZD-2281), lucaparib (PF-01367338), niraparib (MK-4827), talazoparib (BMN-673), veliparib (ABT-888), CEP9722, E7016, BGB-290, and 3-aminobenzamide.

[0020] Examples of TLR agonists include TLR3, TLR4, TLR7, TLR8, and TLR9 agonists. More specific TLR agonists include TLR7 / 8 agonists selected from imidazoquinoline derivatives (IMDs) (e.g., imiquimod, reximod (R848), gardikimod, 852-A (PF-4878691), MEDI9197, etc.), pteridinone derivatives (e.g., vesatolimod (GS-9620)), 8-oxoadenine derivatives (e.g., AZD-8848, etc.), TMX-202, benzazepine analogs (e.g., motlimod (VTX-2337), etc.), and pyrimidine analogs (e.g., selgantolimod (GS-9688, etc.)). More specific TLR9 agonists include CpG oligodeoxynucleotides (e.g., agatrimod), lefitolimod (MGN1703), and tilsotolimod.

[0021] In some embodiments, the immunotherapeutic agents used in the present disclosure include small molecule (i.e., having a molecular weight of less than 3000 Daltons) PARP inhibitors and / or TLR agonists. In some embodiments, the immunotherapeutic agents are dispersed in particulate form throughout biodegradable polymer microspheres. For example, the immunotherapeutic agents can be in the form of nanoparticles having a size of 100 nm to 2000 nm, more typically a size such as 250 nm to 1000 nm. Such particle sizes can be achieved, for example, by grinding the immunotherapeutic agents to the desired size.

[0022] Biodegradable polymer microspheres can be made by many techniques known to those skilled in the art, such as single and double emulsion techniques, solvent evaporation techniques, suspension polymerization techniques, solvent extraction techniques, and combinations thereof. In certain embodiments, including the embodiments described herein, the biodegradable polymer microspheres are made by an emulsion-solvent evaporation technique. The biodegradable polymer microspheres of the present disclosure are particularly useful for embolization because the size of the microspheres can be controlled, for example, by sieving techniques or other classification / fractionation techniques. Further, due to the spherical shape of the biodegradable polymer microspheres, unwanted aggregation can be avoided.

[0023] The biodegradable polymer microspheres can have a range of loading amounts. In some embodiments, the biodegradable polymer microspheres contain 1 to 20 wt% (dry weight) of the immunotherapeutic agent, more typically 3 to 10 wt% (dry weight) of the immunotherapeutic agent.

[0024] The biodegradable polymer microspheres can have a wide range of particle sizes. For example, the biodegradable polymer microspheres can be 10 μm to 500 μm in diameter, typically 30 to 200 μm in diameter, more typically 60 to 150 μm in diameter.

[0025] The biodegradable polymer microspheres can biodegrade in vivo by various processes including bulk erosion and surface erosion. The biodegradable polymer microspheres contain one or more types of biodegradable polymers. In some embodiments, the biodegradable polymer degrades by hydrolysis. In some embodiments, the biodegradable polymer is a biodegradable polyester.

[0026] Examples of biodegradable polyesters include polylactic acids such as polylactic acid (PLA), polyglycolic acids such as polyglycolic acid (PLG), polyhydroxyalkanoates such as polyhydroxybutyrate or polyhydroxyvalerate, polylactones such as poly-γ-butyrolactone, poly-σ-valerolactone, or poly-ε-caprolactone, poly(alkene dicarboxylates) such as poly(butylene succinate) or poly(butylene adipate), poly(p-dioxanone), poly(trimethylene carbonate), and copolymers containing any combination of two, three, or more of the monomers in the preceding polymers ((lactic acid-glycolic acid) copolymer (PLGA), (3-hydroxybutyrate-3-hydroxyvalerate) copolymer, and (butylene succinate-adipate) copolymer, etc.).

[0027] In some embodiments, the biodegradable polymer microspheres contain 80 to 99% by weight (dry weight) of one or more biodegradable polyesters, and more typically, 90 to 97% by weight (dry weight) of one or more biodegradable polyesters.

[0028] [[ID=I3]]The biodegradable polyesters can be employed in various molecular weights, for example, having a number average molecular weight of 500 to 250,000 daltons, and in some embodiments, 1000 to 20,000 daltons.

[0029] Biodegradable polyesters can be terminated with various functional groups including one or more carboxylate-terminated polyesters (e.g., acid-terminated PLGAs containing carboxylate-terminated groups), one or more ester-terminated polyesters (e.g., ester-terminated PLGAs such as methyl ester-terminated PLGAs, ethyl ester-terminated PLGAs, propyl ester-terminated PLGAs, etc.), or one or more hydroxyl groups.

[0030] Biodegradable copolyesters can have a variety of monomer ratios. For example, a biodegradable copolyester having two monomers can have monomer ratios such as 1:99, 10:90, 25:75, 35:65, 50:50, 65:35, 75:25, 90:10, and 99:1 (i.e., within a range between any two of the preceding ratios).

[0031] In certain beneficial embodiments, the biodegradable polymer microsphere comprises two or more types of biodegradable polyesters. Examples include: (a) combinations of multiple biodegradable polyesters formed from multiple different monomers (e.g., a combination of PLA and PLGA); (b) combinations of multiple biodegradable polyesters formed from (one or more) the same monomers but having different molecular weights; (c) combinations of multiple biodegradable polyesters formed from (one or more) the same monomers but having different terminal groups (e.g., a combination of carboxylate-terminated PLGA and ester-terminated PLGA); (d) combinations of multiple biodegradable copolymers formed from the same monomers but having different monomer ratios (e.g., a combination of 50:50 PLGA and 75:25 PLGA); and (e) combinations of any two or all three of the preceding combinations (b), (c), and (d).

[0032] The biodegradable polymer microspheres of this disclosure may be stored and transported as a sterile, dry composition. This dry composition may be transported, for example, in syringes, vials, ampoules, catheters, or other containers (e.g., any container configured to interact with a needle or delivery catheter). The dry composition may be mixed with a suitable liquid carrier (e.g., a solution containing sterile water for injection, saline, phosphate buffer, or imaging contrast agent) before administration. In this method, the concentration of the biodegradable polymer microspheres in the composition to be injected can be freely varied as desired by the healthcare professional administering the treatment, depending on the specific application at present. The liquid carrier in one or more containers may also be supplied and transported in kit form along with the dry particles.

[0033] The biodegradable polymer microspheres may be stored in a sterile liquid suspension containing the biodegradable polymer microspheres and an aqueous or non-aqueous liquid, provided that no unacceptable level of degradation occurs (in relation to the properties of the polymer, the properties of the solution, the shelf life requirements, etc.). Similar to the dry composition, this liquid suspension may be stored in, for example, syringes, vials, ampoules, catheters, or other containers. The liquid suspension may also be mixed with a suitable liquid carrier (e.g., sterile water for injection, saline, phosphate buffer, a solution containing a contrast agent, etc.) before administration, and the concentration of the biodegradable polymer microspheres in the suspension to be administered may be reduced before injection, if desired by the healthcare professional. Liquid carriers in one or more containers may also be supplied to form a kit.

[0034] The dry composition or liquid suspension containing the biodegradable polymer microspheres may optionally also contain additional agents (selected from, for example, imaging agents, tension adjusters, suspending agents, wetting agents, pH adjusters, and colorants). Examples of imaging agents include (a) fluorescent dyes (fluorescein, indocyanine green, or fluorescent proteins (e.g., green, blue, cyan fluorescent proteins)), (b) contrast agents for use in combination with magnetic resonance imaging (MRI), comprising a contrast agent containing elements that form paramagnetic ions such as Gd(III), Mn(II), Fe(III) and element-containing compounds (including complexes) that form paramagnetic ions (e.g., gadolinium complexed with diethylenetriaminepentaacetic acid), (c) contrast agents for use in combination with ultrasound imaging, comprising organic and inorganic echogenic particles (i.e., particles that cause an increase in reflected ultrasound energy) or organic and inorganic echolucent particles (i.e., particles that cause a decrease in reflected ultrasound energy), and (d) contrast agents for use in combination with near-infrared (NIR) imaging, which may be selected to impart near-infrared fluorescence to the hydrogel of this disclosure, thereby enabling imaging of deep tissues and marking of devices. (e) contrast agents (e.g., NIR-sensitive nanoparticles (gold nanoshells, carbon nanotubes (e.g., nanotubes derivatized with hydroxyl or carboxyl groups, e.g., partially oxidized carbon nanotubes, etc.), dye-containing nanoparticles (dye-doped nanofibers and dye-encapsulated nanoparticles, etc.), and semiconductor quantum dots, etc.) and NIR-sensitive dyes (cyanine dyes, squalenes, phthalocyanines, porphyrin derivatives, and boron dipyromethane (BODIPY) analogs, etc.)) (e) imaging radioisotopes (9 (f) (e.g., 9mTc, 201Th, 51Cr, 67Ga, 68Ga, 111In, 64Cu, 89Zr, 59Fe, 42K, 82Rb, 24Na, 45Ti, 44Sc, 51Cr, and 177Lu, etc.), and (f) (e.g., contrast agents) (e.g., metal particles (e.g., particles of tantalum, tungsten, rhenium, niobium, molybdenum and their alloys), which may be spherical or non-spherical), nonionic contrast agents (e.g., iohexol, iodixanol,ioversol, iopamidol, ioxilan, or iopromide, etc.; ionic radiocontrast agents (e.g., diatrizoate, iothalamate, metrizoate, or ioxaglate, etc.); and iodized oils (including ethiodized poppyseed oil (marketed as Lipiodol®)).

[0035] Examples of additional agents include tonicity adjusters (sugars (e.g., dextrose, lactose, etc.), polyhydric alcohols (e.g., glycerol, propylene glycol, mannitol, sorbitol, etc.), and inorganic salts (e.g., potassium chloride, sodium chloride, etc.)), suspending agents (including various surfactants, wetting agents, and polymers (e.g., albumen, PEO, polyvinyl alcohol, block copolymer, etc.)), and pH adjusters (including various buffer solutes). Examples of colorants include brilliant blue (e.g., Brilliant Blue FCF, also known as FD&C Blue 1), indigo carmine (also known as FD&C Blue 2), indigo carmine lake, FD&C Blue 1 lake, and methylene blue (also known as methylthionium chloride).

[0036] In various embodiments, kits are provided that include one or more delivery devices for delivering the biodegradable polymer microspheres of this disclosure to a subject. Such kits may include one or more of the following: a syringe barrel (which may or may not contain the biodegradable polymer microspheres described above); a vial (which may or may not contain the biodegradable polymer microspheres described above); a needle; a flexible tube (e.g., a catheter); a guidewire; and an injectable liquid (such as a solution containing water for injection, ordinary saline, phosphate-buffered saline, or an imaging contrast agent). If supplied, a catheter may be used to inject the biodegradable polymer microspheres into the patient's blood vessels, and a guidewire may be used to position the catheter within the blood vessels. Whether supplied in a syringe, vial, or other reservoir, the biodegradable polymer microspheres may be provided in the form of a dry composition or a liquid suspension as described above.

[0037] In various embodiments, compositions comprising the biodegradable polymer microspheres of the Disclosure are in a sterile state. These compositions can be sterilized by any known method in the art (e.g., radiation irradiation such as gamma, beta, or X-ray irradiation). In certain embodiments, the biodegradable polymer microspheres are prepared aseptically using aseptic techniques.

[0038] In other embodiments, the Disclosure provides a method for treating a patient having a solid tumor, comprising delivering a composition comprising the biodegradable polymer microspheres of the Disclosure (e.g., a liquid suspension of the biodegradable polymer microspheres) to the solid tumor. Examples of solid tumors include solid tumors of the liver, pancreas, uterus, brain, kidney, bone, breast, bladder, prostate, colorectal cancer, lung, oral and / or cervical, esophageal, endometrial, ovarian, gastric, and stomach. The amount of immunotherapy agent delivered to the solid tumor can be varied depending on, for example, the specific immunotherapy agent administered, the type of tumor, the size of the tumor, and the patient's condition. In some embodiments, the solid tumor may be further treated with radiotherapy.

[0039] Methods for administering the biodegradable polymer microspheres include, for example, transdermal methods, as well as other effective routes of administration. For example, in some embodiments, compositions comprising the biodegradable polymer microspheres of the present disclosure may be delivered by direct injection into a tumor. For example, the biodegradable polymer microspheres may be delivered by a needle of 24 gauge or less.

[0040] In some embodiments, compositions comprising the biodegradable polymer microspheres of the present disclosure are delivered via one or more blood vessels (e.g., nutrient arteries) supplying nutrients to at least a portion of a tumor, and at least a portion of the biodegradable polymer microspheres remain within those blood vessels to cause embolism. For example, the biodegradable polymer microspheres may be delivered through a catheter having a size range of, for example, 1.2 Fr (0.4 mm) or larger.

[0041] Once delivered to the tumor, the immunotherapy agent is then released locally by hydrolysis-based biodegradation of its biodegradable polymer microspheres. This immunotherapy agent is then delivered locally and in a controlled manner over a period of several days to several weeks. This minimizes systemic distribution while maintaining the dose of the immunotherapy agent locally within the immunotherapeutic window. [Examples]

[0042] The following PLGA products (commercially available from Evonik Industries AG®, Essen, Germany) are used in this embodiment: RESOMER® RG501H, acid-terminated (D,L-lactic acid-glycolic acid) copolymer, molar ratio 50:50, with an intrinsic viscosity of 0.8 to 0.16 dl / g; RESOMER® RG502, ester-terminated (D,L-lactic acid-glycolic acid) copolymer, molar ratio 50:50, molecular weight 7,000 to 17,000, with an intrinsic viscosity of 0.16 RESOMER® RG502H, an acid-terminated (D,L-lactic acid-glycolic acid) copolymer with an intrinsic viscosity of 0.24 dl / g, has a molar ratio of 50:50, a molecular weight of 7,000 to 17,000, and an intrinsic viscosity of 0.16 to 0.24 dl / g; and RESOMER® RG503H, an acid-terminated (D,L-lactic acid-glycolic acid) copolymer with a molar ratio of 50:50, and an intrinsic viscosity of 0.16 to 0.24 dl / g.

[0043] A 2 mL PLGA solution is formed by dissolving PLGA (RG501H:RG502 (weight ratio 50:50) for imiquimod microspheres; RG501H:RG502H(2A) (weight ratio 50:50) or RG501H:RG503H(4A) (weight ratio 50:50) for olaparib microspheres) in dichloromethane (DCM) at a volume of less than 25% w / v. The PLGA was dissolved at ambient temperature with stirring for 30 minutes.

[0044] An immunotherapy agent (imiquimod or olaparib) was pulverized in dichloromethane (DCM) to a size of 500-1000 nm, and then added in various amounts to the PLGA solution until it reached a maximum of 12% by weight relative to the PLGA in the solution, thereby forming a PLGA / immunotherapy agent organic solution.

[0045] A 5 mL PVA solution was prepared by dissolving a surfactant / stabilizer such as polyvinyl alcohol (PVA) in water (e.g., sterile water or deionized water) at a concentration of 2% by weight. This PVA was dissolved at a maximum temperature of 80°C for 1 hour or until completely dissolved, with vigorous stirring.

[0046] Then, the PLGA / immunotherapy organic solution was added dropwise or with a standardized needle to the PVA aqueous solution at ambient temperature while stirring at 300 rpm. The resulting mixture was then homogenized for 5 minutes to form an oil-in-water emulsion. This emulsion was diluted with approximately twice the volume of sterile water and incubated overnight at ambient temperature (25°C) while stirring at 150 rpm.

[0047] The resulting microsphere mixture was then added to 250 mL of 1% PVA solution and incubated at 31°C and 80 rpm for 48 hours. This liquid phase was separated by tilt, and the biodegradable polymer microspheres were washed with 100 mL of sterile water. This washing step was repeated three times. The resulting microspheres are shown in Figure 1.

[0048] The microspheres were then separated using a 150 μm sieve and then a nylon mesh woven with 80 μm or 100 μm threads, resulting in particles ranging from 80 to 150 μm or 100 to 150 μm. These sorted particles were then dried under vacuum at ambient temperature for over 12 hours.

[0049] Acetate buffer (approximately pH 4) was prepared by dissolving 0.93 g of sodium acetate and 2.321 mL of glacial acetic acid in 500 mL of water. The immunotherapy agent content in biodegradable polymer microspheres was determined by weighing approximately 1 mg of biodegradable polymer microspheres into a vial, adding 10 mL of acetonitrile (ACN):acetic acid buffer (1:1), dissolving the biodegradable polymer microspheres, and performing UV-Vis spectroscopy (wavelength = 241 nm or 319 nm for imiquimod; wavelength = 253 nm for olaparib). The concentration of the immunotherapy agent (μg / mL-solution) was calculated using the slope of a previously prepared standard of the immunotherapy agent. From this concentration, the percentage of immunotherapy agent content in the biodegradable polymer microspheres was calculated. It was found that the imiquimod content in the biodegradable polymer microspheres was approximately 7% by weight, and the olaparib content was approximately 5% by weight.

[0050] The kinetic drug release from biodegradable polymer microspheres is measured by weighing approximately 1 mg of biodegradable polymer microspheres into a centrifuge tube, adding 10 mL of PBS Tween, and incubating on a shaker at 37°C and 120 rpm. At each point in time of interest (e.g., days 3, 7, 10, 14, and 21), the biodegradable polymer microspheres are allowed to settle by centrifugation, and the medium is removed by pipette. Subsequently, 5 mL of ACN:acetic acid buffer (pH 4) (1:1) is added directly to the biodegradable polymer microspheres, and UV-Vis spectroscopy is performed. The measured immunotherapy concentration is used to calculate the percentage of immunotherapy remaining in the biodegradable polymer microspheres. The results of the kinetic drug release are shown in Figure 2.

Claims

1. A biodegradable polymer microsphere comprising a biodegradable polymer and an immunotherapy agent selected from a poly-ADP-ribose polymerase enzyme inhibitor (PARP inhibitor) and / or a Toll-like receptor (TLR) agonist, wherein (a) 50% of the total amount of the immunotherapy agent in the biodegradable polymer microsphere is released from the biodegradable polymer microsphere into a PBS Tween 20 (0.05%) solution at 37°C at some point between 3 and 14 days; (b) 1 mg to 100 mg of the immunotherapy agent per gram of dry weight of the microsphere is released from the biodegradable polymer microsphere into a PBS Tween 20 (0.05%) solution at 37°C at some point between 3 and 14 days; or (c) both of (a) and (b).

2. The biodegradable polymer microspheres according to claim 1, wherein the immunotherapy agent is dispersed throughout the particles in the form of nanoparticles having a size of 100 nm to 2000 nm.

3. The biodegradable polymer microsphere according to claim 1 or 2, comprising 3% to 10% by weight of the immunotherapy agent based on the dry weight of the biodegradable polymer microsphere.

4. The biodegradable polymer microsphere according to any one of claims 1 to 3, wherein the biodegradable polymer microsphere has a diameter of 30 to 200 μm.

5. The immunotherapy agent is released by bulk erosion and hydrolysis in the biodegradable polymer microsphere according to any one of claims 1 to 4.

6. The biodegradable polymer microsphere according to any one of claims 1 to 5, wherein the biodegradable polymer is a biodegradable polyester.

7. The biodegradable polymer microsphere according to any one of claims 1 to 6, wherein the biodegradable polymer consists of or contains a (lactic acid-glycolic acid) copolymer (PLGA).

8. The biodegradable polymer microsphere according to claim 7, wherein the ratio of lactic acid units to glycolic acid units in the PLGA is 60:40 to 40:

60.

9. The biodegradable polymer microsphere according to claim 7, wherein the ratio of lactic acid units to glycolic acid units in the PLGA is 50:

50.

10. The biodegradable polymer microsphere according to any one of claims 7 to 9, wherein the PLGA includes acid-terminated PLGA.

11. The biodegradable polymer microsphere according to any one of claims 7 to 9, wherein the PLGA includes a combination of acid-terminated PLGA and ester-terminated PLGA.

12. A biodegradable polymer microsphere according to any one of claims 1 to 11, further comprising a pharmaceutical excipient selected from the group consisting of a preservative, a tension modifier, a viscosity modifier, a pH modifier, a contrast agent, a surfactant, or a sugar or sugar alcohol.

13. The biodegradable polymer microsphere according to any one of claims 1 to 12, wherein the biodegradable polymer microsphere is provided in a dry form.

14. The biodegradable polymer microsphere according to any one of claims 1 to 12, wherein the biodegradable polymer microsphere is provided in an aqueous liquid.

15. The biodegradable polymer microsphere according to any one of claims 1 to 14, wherein the biodegradable polymer microsphere is provided in a vial or syringe.

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