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US-20260125436-A1 - IL-12 PRODRUGS, METHODS OF USE AND PHARMACEUTICAL COMPOSITIONS

US20260125436A1US 20260125436 A1US20260125436 A1US 20260125436A1US-20260125436-A1

Abstract

This disclosure relates to methods and compositions for treating cancer including advanced solid tumor, a metastatic solid tumor or lymphoma using an inducible IL-12 prodrug.

Inventors

  • Randi Isaacs
  • Sameer Chopra
  • Kulandayan Subramanian

Assignees

  • WEREWOLF THERAPEUTICS, INC.

Dates

Publication Date
20260507
Application Date
20250911

Claims (20)

  1. 1 . A method for treating an advanced solid tumor, a metastatic solid tumor or a lymphoma, comprising administering to a subject in need thereof an inducible IL-12 prodrug comprising Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, Compound 16, Compound 17, Compound 18, Compound 19, Compound 20, Compound 21, Compound 22, Compound 23, Compound 24, Compound 25, Compound 26, Compound 27, Compound 28, Compound 29, Compound 30, Compound 31, Compound 32, Compound 33, Compound 34, Compound 35, or Compound 36 or an amino acid sequence variant of the foregoing.
  2. 2 . The method of claim 1 , wherein the administration is oral, parenteral, intravenous, intra-articular, intraperitoneal, intramuscular, subcutaneous, intracavity, transdermal, intrahepatical, intracranial, nebulization/inhalation, by installation via bronchoscopy, or intratumoral.
  3. 3 . The method of claim 2 , wherein the administration is intravenous.
  4. 4 . The method of claim 1 , wherein the inducible IL-12 prodrug is administered about twice a week or less frequently, about once a week or less frequently, or about once every 2 weeks.
  5. 5 . (canceled)
  6. 6 . (canceled)
  7. 7 . The method of claim 1 , wherein about 0.016 mg/kg, about 0.032 mg/kg, about 0.056 mg/kg, about 0.084 mg/kg, about 0.126 mg/kg, about 0.190 mg/kg, about 0.290 mg/kg, or about 0.440 mg/kg of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, Compound 16, Compound 17, Compound 18, Compound 19, Compound 20, Compound 21, Compound 22, Compound 23, Compound 24, Compound 25, Compound 26, Compound 27, Compound 28, Compound 29, Compound 30, Compound 31, Compound 32, Compound 33, Compound 34, Compound 35, or Compound 36 or an amino acid sequence variant of the foregoing is administered every two weeks.
  8. 8 - 15 . (canceled)
  9. 16 . The method of claim 1 , wherein about 1 mg, about 3 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 100 mg, or about 200 mg of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, Compound 16, Compound 17, Compound 18, Compound 19, Compound 20, Compound 21, Compound 22, Compound 23, Compound 24, Compound 25, Compound 26, Compound 27, Compound 28, Compound 29, Compound 30, Compound 31, Compound 32, Compound 33, Compound 34, Compound 35, or Compound 36 or an amino acid sequence variant of the foregoing is administered every two weeks.
  10. 17 . (canceled)
  11. 18 . The method of claim 1 , wherein the subject has failed to achieve a complete response to a prior treatment or to an ongoing treatment.
  12. 19 . The method of claim 16 , wherein the prior or ongoing treatment comprises treatment with a checkpoint inhibitor, and the checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTL4-A antibody.
  13. 20 . (canceled)
  14. 21 . (canceled)
  15. 22 . The method of claim 1 , wherein the advanced solid tumor, the metastatic solid tumor or the lymphoma is adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, basal cell carcinoma, brain tumor, bile duct cancer, bladder cancer, bone cancer, breast cancer, bronchial tumor, carcinoma of unknown primary origin, cardiac tumor, cervical cancer, chordoma, colon cancer, colorectal cancer, craniopharyngioma, ductal carcinoma, embryonal tumor, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, fibrous histiocytoma, Ewing sarcoma, eye cancer, germ cell tumor, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, gestational trophoblastic disease, glioma, head and neck cancer, hepatocellular cancer, histiocytosis, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ, lung cancer, macroglobulinemia, malignant fibrous histiocytoma, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer with occult primary, midline tract carcinoma involving NUT gene, mouth cancer, multiple endocrine neoplasia syndrome, mycosis fungoides, myelodysplastic syndrome, myelodysplastic/myeloproliferative neoplasm, nasal cavity and par nasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-small cell lung cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytomas, pituitary tumor, pleuropulmonary blastoma, prostate cancer, rectal cancer, renal cell cancer, renal pelvis and ureter cancer, retinoblastoma, rhabdoid tumor, salivary gland cancer, Sezary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, spinal cord tumor, stomach cancer, T-cell lymphoma, teratoid tumor, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, vaginal cancer, vulvar cancer, and Wilms tumor.
  16. 23 . (canceled)
  17. 24 . (canceled)
  18. 25 . The method of claim 1 , wherein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, Compound 16, Compound 17, Compound 18, Compound 19, Compound 20, Compound 21, Compound 22, Compound 23, Compound 24, Compound 25, Compound 26, Compound 27, Compound 28, Compound 29, Compound 30, Compound 31, Compound 32, Compound 33, Compound 34, Compound 35, or Compound 36 or an amino acid sequence variant of the foregoing is administered concurrently with the anti-PD-1 antibody, or antigen binding fragment thereof.
  19. 26 . A pharmaceutical composition comprising an inducible IL-12 prodrug, a citric acid and/or a citrate salt, a disaccharide and a surfactant.
  20. 27 . The pharmaceutical composition of claim 26 wherein the citrate salt is sodium citrate, magnesium citrate or potassium citrate; the disaccharide is sucrose, trehalose, lactose or maltose, and the surfactant is a nonionic surfactant selected from polysorbate 80, polysorbate 20, Span-80, castor oil, or a poloxamer.

Description

The present application is a continuation of International Patent Application No. PCT/US2024/023550, filed Jun. 27, 2024, which designated the United States, which claims the benefit of U.S. Provisional Application No. 63/494,517, filed on Apr. 6, 2023, and U.S. Provisional Application No. 63/495,899, filed on Apr. 13, 2023, the entire contents of each of which are incorporated herein by reference in their entireties. 1. SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on Apr. 5, 2024, is named 761146_292320_SL.xml and is 277 bytes in size. 2. BACKGROUND Cancer immunotherapy has rapidly established itself as the fourth pillar of cancer treatment largely owing to the clinical success of checkpoint inhibitors. Despite the durable responses achieved by some patients using these new therapies, the proportion of responders is still relatively low and restricted to only some cancer types. Tumor mutational burden, the presence or absence of T cell infiltration in tumors, and the overall immunosuppressive microenvironment of tumors greatly influences the response to immunotherapies. Although immune checkpoint blockade can prevent the physiological stop-signal that arises in response to immune activation, other approaches can be used to positively stimulate the anti-tumor immune response. One approach involves the use of immune-activating cytokines. Numerous preclinical and clinical studies have demonstrated the promise of cytokine therapy to increase anti-tumor immunity. In fact, these were some of the first cancer immunotherapies approved for clinical use. However, systemic toxicity and poor pharmacokinetic profiles have limited their clinical application. Interleukin-12 (IL-12) is a heterodimeric 70 kDa cytokine composed of two covalently linked glycosylated subunits (p35 and p40) (Lieschke et al., 1997; Jana et al., 2014). It is a potent immune agonist and has been considered a promising therapeutic agent for oncology. However, IL-12 has shown to have a narrow therapeutic window because they are highly potent and have a short serum half-life. Consequently, therapeutic administration of IL-12 produces undesirable systemic effects and toxicities. This is exacerbated by the need to administer large quantities of cytokines (i.e., IL-12) in order to achieve the desired levels of cytokine at the intended site of cytokine action (e.g., a tumor microenvironment). Unfortunately, due to the biology of cytokine and the inability to effectively target and control their activity, cytokines have not achieved the hoped for clinical advantages in the treatment in tumors. Inducible forms of IL-12, that are conditionally activated in the tumor microenvironment through protease cleavage to release the fully active, native IL-12 cytokine within the tumor to stimulate a potent anti-tumor immune response, are described in International Application Nos. PCT/US2019/032320, PCT/US2019/032322, and PCT/US2021/033014. These IL-12 prodrugs include a native IL-12 molecule attached through a protease cleavable linker to a half-life extension domain (e.g., anti-human serum albumin antibody binding fragment such as a VH domain) and an IL-12 blocking element (e.g., anti-IL-12 antibody binding fragment, such as a Fab or scFv) to block binding of IL-12 to IL-12Rβ1 or IL-12Rβ2 receptors on normal tissue in the periphery. Upon cleavage of the protease cleavable linker, fully active native IL-12 is released within the tumor to stimulate a potent anti-tumor immune response. 3. SUMMARY This disclosure relates to compositions and methods for treating cancer using an inducible IL-12 prodrug. The inducible IL-12 prodrug that contain an attenuated IL-12 and that have a long half-life in comparison to naturally occurring IL-12. If desired, the IL-12 can be a mutein. The IL-12 mutein can be aglycosylated or partially aglycosylated. The inducible IL-12 prodrugs disclosed herein comprise two or more polypeptide chains, and the inducible IL-12 prodrug includes IL-12 subunits p35 and p40, a half-life extension element, an IL-12 blocking element and a protease cleavable linker. The inducible IL-12 prodrug can comprise two different polypeptides. The first polypeptide can comprise an IL-12 subunit, and optionally an IL-12 blocking element. The IL-12 blocking element when present is operably linked to the IL-12 subunit through a first protease cleavable linker. The second polypeptide chain can comprise an IL-12 subunit operably linked to a half-life extension element through a second protease cleavable linker, and optionally a IL-12 blocking element. The IL-12 blocking element when present can be operably linked to the IL-12 subunit through a protease cleavable linker or can be operably linked to the half-life extension element through a linker that is optionally protease cleavable. Only one of the first and secon