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US-20260124210-A1 - THERAPEUTIC CONSTRUCTS FOR CO-DELIVERY OF ANTI-CANCER AGENT(S) AND IMMUNE CHECKPOINT INHIBITOR(S)

US20260124210A1US 20260124210 A1US20260124210 A1US 20260124210A1US-20260124210-A1

Abstract

Disclosed herein are therapeutic constructs including a delivery particle, at least one anti-cancer agent (e.g., a mitotic kinase inhibitor), and at least one immune checkpoint inhibitor. Also disclosed are therapeutic constructs including a mitotic kinase inhibitor, an immune checkpoint inhibitor, and a chemical linker. These therapeutic constructs cause cancer death by both therapeutic and immune effects and promote targeted delivery of more therapeutics to the surviving cancer cells in a positive feed-back loop. They enhance therapeutic index of free drugs and can be used intratumorally or systemically. This strategy can treat broad cancer types and is particular useful for cancer without obvious receptors for cancer-targeted delivery of otherwise toxic therapeutics.

Inventors

  • Wassana Yantasee
  • Moataz REDA
  • Worapol NGAMCHERDTRAKUL

Assignees

  • OREGON HEALTH & SCIENCE UNIVERSITY
  • PDX PHARMACEUTICALS, INC.

Dates

Publication Date
20260507
Application Date
20251230

Claims (20)

  1. 1 . A therapeutic construct comprising: a mesoporous silica nanoparticle (MSNP) comprising platform loaded with: an anti-cancer agent in an amount 0.1% to 20% by weight of the therapeutic construct; and an antibody specific for an immune checkpoint protein.
  2. 2 . The therapeutic construct of claim 1 , wherein the anti-cancer agent comprises at least one of a PLK1 inhibitor, PLK2 inhibitor, PLK3 inhibitor, PLK4 inhibitor, CDK1 inhibitor, CDK2 inhibitor, CHK1 inhibitor, CHK2 inhibitor, BUB1 inhibitor, BUBR1 inhibitor, MPS1 inhibitor, NEK2 inhibitor, HASPIN inhibitor, an Aurora kinase inhibitor, Wee1 kinase inhibitor, PARP inhibitor, MEK inhibitor, CDK4/6 inhibitor, EGFR inhibitor, HER2 inhibitor, VEGF inhibitor, BRAF inhibitor, PI3K inhibitor, mTOR inhibitor, or ras inhibitor.
  3. 3 . The therapeutic construct of claim 1 , wherein the anti-cancer agent comprises one or more of: a peptide, an antibody or fragment thereof, a nucleic acid or derivative thereof, a small inorganic molecule, a cytotoxic chemotherapy drug, an alkylating agent, an anti-metabolite, a plant alkaloid, a tyrosine kinase inhibitor a topoisomerase inhibitor, an antibiotic, a angiogenesis-inhibiting enzyme, an antisense oligonucleotide, an immunostimulant peptide, a nitric oxide modulator, a steroid, a monoclonal antibody, an immunotoxin, a radioimmunotherapeutic agent, or an immune-checkpoint inhibitor.
  4. 4 . The therapeutic construct of claim 1 , wherein the anti-cancer agent comprises at least one of etoposide, vinorelbine, mitoxantrone, doxorubicin, estramustine, carboplatin, vinblastine, docetaxel, paclitaxel, cisplatin, methotrexate, oxaliplatin, 5-fluorouracil, or cabazitaxel.
  5. 5 . The therapeutic construct of claim 1 , wherein the anti-cancer agent comprises one or more siRNAs specific for at least one of PLK1, PLK2, PLK3, PLK4, CDK1, CDK2, CHK1, CHK2, BUB1, BUBR1, MPS1, NEK2, HASPIN, an Aurora kinase, Wee1 kinase, STAT3, TGF-β, CD47, NOX1-5, HSP47, XBP1, BCL2, BCL-XL, AKT1, AKT2, AKT3, MYC, HER2, HER3, AR, Survivin, GRB7, EPS8L1, RRM2, PKN3, EGFR, IRE1-alpha, VEGF-R1, RTP801, proNGF, Keratin K6A, LMP2, LMP7, MECL1, HIF1α, Furin, KSP, eiF-4E, p53, β-catenin, ApoB, PCSK9, SNALP, CD39, CD73, MIF, VEGF, PIGF, CXCR4, CCR2, MTDH, Twist, Lcn2, IL-6, IL-10, or p65.
  6. 6 . The therapeutic construct of claim 1 , wherein the MSNP is coated with cross-linked polyethylenimine (PEI) and polyethylene glycol.
  7. 7 . The therapeutic construct of claim 1 , wherein the antibody makes up 0.1% to 20% by weight of the therapeutic construct.
  8. 8 . The therapeutic construct of claim 1 , wherein, the antibody is conjugated onto the MSNP comprising platform.
  9. 9 . The therapeutic construct of claim 1 , wherein the MSNP has a mean particle size of about 30 nm to about 80 nm.
  10. 10 . The therapeutic construct of claim 1 , having a hydrodynamic size of about 80 nm to about 200 nm.
  11. 11 . The therapeutic construct of claim 1 , further comprising an adjuvant.
  12. 12 . The therapeutic construct of claim 11 , wherein the adjuvant comprises at least one of a CpG oligonucleotide, stimulator of IFN gene (STING) agonist, or a RIG-1 helicase activator.
  13. 13 . The therapeutic construct of claim 12 , wherein the adjuvant comprises a CpG oligonucleotide, and the CpG oligonucleotide is CpG ODN 7909.
  14. 14 . A composition comprising: the therapeutic construct of claim 1 ; and a pharmaceutically acceptable carrier, excipient, or diluent.
  15. 15 . A method of treating a subject diagnosed as having a hyperproliferative disease or condition, comprising administering to the subject an effective amount of the composition of claim 14 .
  16. 16 . The method of claim 15 , wherein the subject is a mammal.
  17. 17 . The method of claim 16 , wherein the mammal is a human.
  18. 18 . The method of claim 17 , wherein the hyperproliferative disease comprises one or more of cancer, precancer, or cancer metastasis.
  19. 19 . The method of claim 18 , wherein the hyperproliferative disease comprises one or more of melanoma, lung cancer, breast cancer, pancreatic cancer, brain cancer, prostate cancer, head and neck cancer, kidney cancer, colorectal cancer, lymphoma, colon cancer, ovarian cancer, or liver cancer.
  20. 20 . The method of claim 19 , wherein administering comprises one or more of: injection to or at a tumor in the subject; infusion locally to or at a tumor in the subject; systemic injection in the subject; systemic infusion in the subject; oral administration to the subject; topical application to the subject; intravenous injection; or intratumoral injection.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This is a continuation of co-pending U.S. application Ser. No. 18/763,746, filed Jul. 3, 2024; which is a continuation of U.S. application Ser. No. 18/315,448, filed May 10, 2023, issued on Aug. 13, 2024 as U.S. Pat. No. 12,059,500; which is a continuation of U.S. application Ser. No. 17/534,415, filed Nov. 23, 2021, issued on Jun. 20, 2023 as U.S. Pat. No. 11,679,082; which is a continuation of U.S. application Ser. No. 17/023,311, filed Sep. 16, 2020, issued on Jan. 18, 2022 as U.S. Pat. No. 11,224,573; which is a continuation of International Application No. PCT/US2020/041852, filed Jul. 13, 2020; which in turn claims priority to and the benefit of the earlier filing date of U.S. Provisional Application No. 62/873,770, filed on Jul. 12, 2019. Each of these earlier filed applications is incorporated by reference herein in its entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under grant R44CA217534 awarded by the National Institutes of Health. The government has certain rights in the invention. INCORPORATION BY REFERENCE OF SEQUENCE LISTING A computer readable .XML file, entitled “0046-0033USC4_SeqList.xml” created on or about Dec. 29, 2025, with a file size of 8,192 bytes, contains the sequence listing for this application and is hereby incorporated by reference in its entirety. FIELD OF THE DISCLOSURE The current disclosure relates to compositions and methods for immunotherapy treatment. Therapeutic constructs are described based on co-delivery of anti-cancer agent(s) (such as a mitotic kinase inhibitor) and immune checkpoint inhibitor(s). These therapeutic constructs have greater therapeutic index and/or trigger adaptive anti-cancer immunity better than the free drug counterparts for broad cancer treatment. BACKGROUND OF THE DISCLOSURE Immune checkpoint inhibitors, such as antibodies against PD-L1, PD-1, and CTLA-4 have shown promising outcomes in clinics, gaining fast track FDA approval for treating many cancer types. However, while patients who respond to immune checkpoint blockade may show robust and durable responses, only a minority of total patients respond, and even for patients with high PD-L1 expression, response rates remain under 50% (Reck et al., NEJM 375(19):1823-1833, 2016). Furthermore, many initial responders will develop resistance and ultimately relapse (Jenkins et al., Brit J Canc. 118:9, 2018). While in general immune checkpoint blockade has less severe and distinct toxicity from chemotherapy, autoimmune disorders caused by immunotherapy are a concern (Tocut et al., Autoimmunity Rev 17(6):610-616, 2018). Systemic distribution of these antibodies can cause aberrant and uncontrolled immune response, leading to immune-related adverse effects (irAEs) (Reynolds et al., J Clin Oncol. 36(16_suppl):3096, 2018). While generally manageable, discontinuation of treatment due to irAEs has occurred and in some instances irAEs can be fatal. To improve cancer treatment outcomes, studies have investigated the use chemotherapy in combination with immune checkpoint inhibitors. For instance, one clinical trial has investigated the combination of nab-paclitaxel (abraxane) with PD-L1 antibody (atezolizumab) given as free agents for metastatic TNBC (Schmid et al., N Engl J Med 379(22):2108-2021, 2018). For preclinical studies, nanoparticle for co-delivery of docetaxel and PD-L1 antibody (Xu et al., Inter J Nanomed. 14:17-32, 2018) or doxorubicin and PD-L1 antibody (Emami et al., Mol Pharm 16(3):1184-1199, 2019) have been reported. However, co-delivery of mitotic kinase inhibitor and an immune checkpoint inhibitor has never been reported as free agents or co-delivered on particles or with chemical linkers. Mitotic kinase inhibitors have single-agent potency to kill cancer cells by inducing cell cycle arrest and apoptosis. Unlike chemotherapeutics which kill any fast dividing cells, mitotic kinase inhibitors are considered targeted therapy, and should be more specific to cancer cells than chemotherapeutics. Nevertheless, major limitations of current mitotic kinase inhibitors such as PLK1 small molecule inhibitors include low solid tumor bioavailability and toxic side effects to other rapidly dividing cells, particularly to hematopoietic precursor cells (Gjertsen & Schoffski, Leukemia 29(1):11-19, 2015). PLK1 inhibitors need to have long half-lives in order to achieve sufficient tumor bioavailability. This results in longer exposure times with hematopoietic precursor cells in blood and bone marrow, which leads to dose-limiting toxicity of neutropenia (low neutrophils) and thrombocytopenia (low platelets) (de Braud et al., Annals of Oncol./EMSO 26(11):2341-2346, 2015; Schoffski et al., Euro J Canc. 48(2):179-186, 2012; Lin et al., Brit J Canc. 110(10):2434-2440, 2014; Frost et al., Curr Oncol. 19(1):e28-35, 2012). This highlights the need for targeted delivery of the mitotic kinase inhibitors to can