JPWO2020160639A5 - - Google Patents

Claims (60)

A method for determining a cancer patient population for treatment with an IL-4-targeted cargo protein, said method comprising:
a) measuring the level of IL-4 receptor (IL-4R) expression in a biological sample obtained from a cancer or tumor in said cancer patient;
b) quantifying the measured level of IL-4R expression in said biological sample;
including
said cancer patient is treated with an IL-4-targeted cargo protein when said level of IL-4R expression is moderate or high;
Method. A method for predicting or determining therapeutic efficacy with an IL-4-targeted cargo protein, said method comprising:
a) measuring the level of IL-4 receptor (IL-4R) expression in vivo from a cancer or tumor in said cancer patient;
b) quantifying the measured level of IL-4R expression in the biological sample;
c) correlating said level of IL-4R with said efficacy of treatment, wherein moderate or high levels of IL-4R expression indicate therapeutic efficacy of treatment with an IL-4 targeting cargo protein; A method comprising correlating. A method for altering a treatment regimen for a patient with cancer, said method comprising:
a) measuring the level of IL-4 receptor (IL-4R) expression in vivo from a cancer or tumor in said cancer patient;
b) quantifying a measure of said level of IL-4R expression in a biological sample, wherein moderate or high levels of IL-4R expression are indicative of therapeutic efficacy;
c) correlating said level of IL-4R expression with said efficacy of treatment, wherein high levels of IL-4R expression alter said therapeutic regimen for treatment with an IL-4 targeting cargo protein. indicating or correlating; and
including
if moderate or high levels of IL-4R expression are measured, said therapeutic regimen is altered to include an IL-4 targeting cargo protein;
Method. A method for predicting or determining prognosis and/or progression of cancer disease, said method comprising:
a) measuring the level of IL-4 receptor (IL-4R) expression in a biological sample from a tumor in a cancer patient;
b) quantifying a measure of said level of IL-4R expression in said biological sample, wherein moderate or high levels of IL-4R expression are indicative of prognosis and/or progression of said disease. and
c) correlating said level of IL-4R expression with prognosis and/or progression of said disease, wherein moderate or high levels of IL-4R expression are indicative of severe disease prognosis and/or progression; A method comprising correlating. 5. The method of claim 4, wherein said cancer patient is treated with an IL-4-targeted cargo protein when high levels of IL-4R expression are measured. 6. The method of any one of claims 1-5 , wherein said level of IL-4R expression is a high level of IL-4R expression. 7. The method of any one of claims 1-6 , wherein high level IL-4R expression is indicated by a percent score of 2+ or higher. 8. The method of any one of claims 1-7 , wherein high level IL-4R expression is indicated by a percent score of 3+ or higher. 9. The method of any one of claims 1-8 , wherein moderate levels of IL-4R expression are indicated by a percentage score of 1 or more but less than 2. The method of any one of claims 1-9 , wherein moderate levels of IL-4R expression are indicated by an H-score of 76-150. The method of any one of claims 1-10 , wherein high level IL-4R expression is indicated by an H-score of 151-225. The method of any one of claims 1-11 , wherein high level IL-4R expression is indicated by an H-score of 226-300. A method according to any one of claims 1 to 12 , wherein said level of IL-4R expression is measured by measuring the level of IL-4Rα expression. 14. The method of any one of claims 1-13 , wherein said level of IL-4R expression is the level of type 2 IL-4R (type II IL-R4, including IL-4Rα and IL13Rα1) expression. 15. The method of any one of claims 1-14, wherein said level of IL-4R expression is measured using immunohistochemical (IHC) staining for IL-4R, including IL-4Rα expression. . said cancer or tumor is prostate cancer, ovarian cancer, breast cancer, endometrial cancer, multiple myeloma, melanoma, lymphoma, lung cancer including small cell lung cancer, kidney cancer, liver cancer, colon cancer cancer, colorectal cancer, pancreatic cancer, gastric cancer , and brain cancer (including CNS tumors). The CNS tumor is glioma, glioblastoma (including glioblastoma multiforme, GBM, and refractory glioblastoma multiforme, rGBM), astrocytoma, medulloblastoma, craniopharyngioma ( craniopharyogioma), ependymoma, pineophyma, hemangioblastoma, acoustic neuroma, oligodendrocyte, menangioma, meningioma, neuroblastoma, retinoblastoma, medulloblastoma , and adult pituitary adenoma. 18. The method of claim 16 or 17, wherein said CNS tumor is glioblastoma. 19. The method of any one of claims 16-18, wherein said CNS tumor is a relapsed or refractory glioblastoma (eg, including rGBM). The method of any one of claims 16-19, wherein the subject has an O6-methylguanine-methyltransferase (MGMT) positive or negative CNS tumor. The method of any one of claims 16-20, wherein the subject has a furin-positive CNS tumor. 22. The method of any one of claims 1-21 , wherein the IL-4 targeting cargo protein comprises one or more cargo moieties. 23. The method of any one of claims 1-22 , wherein the IL-4 targeting cargo protein comprises a toxin. 24. The method of claim 23, wherein said toxin comprises a bacterial, animal or plant toxin. 25. The method of claim 24, wherein said toxin comprises a pore-forming toxin. 26. The method of claim 25, wherein the pore-forming toxin comprises aerolysin or proaerolysin. 25. The method of claim 24, wherein the plant toxin comprises boganin or ricin. 25. The method of claim 24, wherein said bacterial toxin comprises a toxin selected from the group consisting of Pseudomonas exotoxin, cholera toxin, or diphtheria toxin. 4. The IL-4 targeting cargo protein comprises a pro-apoptotic member of the BCL-2 family selected from the group consisting of BAX, BAD, BAT, BAK, BIK, BOK, BID BIM, BMF, and BOK . 29. The method of any one of 1-28 . 30. The method of any one of claims 1-29, wherein said IL-4 targeting cargo protein comprises MDNA55 (SEQ ID NO: 65) or a derivative or variant thereof. 31. The method of any one of claims 1-30 , wherein the IL-4 targeting cargo protein is MDNA55. 32. The method of any one of claims 1-31 , wherein said IL-4 targeting cargo protein comprises an IL-4R antibody as a targeting moiety. 33. The method of claim 32, wherein said IL-4R antibody is a humanized antibody. 34. The method of any one of claims 1-33 , wherein the IL-4 targeting cargo protein comprises a fusion protein. 35. The method of any one of claims 1-34 , wherein the IL-4 targeting cargo protein is administered intratumorally. 35. The method of claim 34, wherein said intratumoral administration comprises intracranial administration. Claims 1-36, wherein said IL-4 targeting cargo protein is a formulation in an artificial cerebrospinal fluid (CSF) solution and albumin, said formulation being co-administered with a surrogate tracer to a subject in need thereof. The method according to any one of . The method of any one of claims 1-37 , wherein said surrogate tracer is a magnetic resonance imaging (MRI) contrast agent. 39. The method of any one of claims 1-38 , wherein the surrogate tracer is a gadolinium-bound tracer. 40. The method of any one of claims 1-39 , wherein said surrogate tracer is selected from the group consisting of gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) and gadolinium-bound albumin (Gd-albumin). The method of any one of claims 1-40 , wherein said albumin is human serum albumin. 42. The method of any one of claims 1-41 , wherein the artificial CSF solution is Elliotts B® solution. 43. The method of any one of claims 1-42 , wherein the IL-4 targeting cargo protein is administered via an intracranial catheter. 44. The method of any one of claims 1-43 , wherein the IL-4 targeted cargo protein is administered by convection enhanced delivery (CED). 45. The method of any one of claims 1-44 , wherein the IL-4 targeted cargo protein is administered as a single dose by convection-enhanced delivery (CED). 46. The method of any one of claims 1-45 , wherein the IL-4 targeting cargo protein is administered as a single dose. The IL-4 targeting cargo protein is administered as a single dose of about 90 μg (1.5 μg/mL in 60 mL), about 240 μg (6 μg/mL in 40 mL), or about 300 μg (3 μg/mL in 100 mL) , a method according to any one of claims 1-46 . 48. The method of claim 47, wherein said IL-4 targeting cargo protein is administered at a dose of 1.5 μg/mL in 60 mL. 48. The method of claim 47, wherein said IL-4 targeting cargo protein is administered at a dose of 6 μg/mL in 40 mL. 48. The method of claim 47, wherein said IL-4 targeting cargo protein is administered at a dose of 3 μg/mL in 100 mL. 51. The method of any one of claims 1-50 , wherein the IL-4 targeting cargo protein is administered as a single dose of about 1.5 μg/mL to about 3 μg/mL. 52. Any of claims 1-51 , wherein the IL-4 targeting cargo protein is administered as a single dose over 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or 8 days. or the method described in paragraph 1. 53. The method of any one of claims 1-52 , wherein the IL-4-targeted cargo protein is administered as 1, 2, 3, 4, or 5 injections. wherein said IL-4 targeting cargo protein is administered according to any one of claims 1-53 and then administration is discontinued for about 1 day to about 8 days, optionally 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or 8 days after administration has been discontinued , administration according to any one of claims 1-53 , wherein the pattern of administration and administration discontinuation is according to said 54. The method of any one of claims 1-53 , repeated for as long as necessary to treat CNS tumors. 55. The method of any one of claims 1-54 , wherein the IL-4 targeting cargo protein is administered via one or more intracranial catheters, including 1-3 catheters. 56. The method of claim 55, wherein the IL-4 targeting cargo protein is administered through the catheter at a flow rate of about 5 μL/min/catheter to about 20 μL/min/catheter or a flow rate of about 15 μL/min/catheter. . 57. The method of claim 56, wherein said IL-4 targeting cargo protein is administered through said catheter at a concentration of 1.5 μg/mL and a flow rate of about 15 μL/min/catheter. 58. The method of any one of claims 1-57 , wherein the steroid is used in combination with an IL-4 targeting cargo protein. 59. The method of claim 58, wherein said steroid is administered at 4 mg/day or less. 60. A kit comprising the IL-4 targeting cargo protein of any one of claims 1-59 , wherein the kit comprises an IL-4R antibody, an immunohistochemistry (IHC) based assay for the IL-4 A kit comprising instructions for using a 4R antibody and instructions for determining said percent score or said H-score.