Methods of treating tumors

Abstract

The disclosure provides pharmaceutical compositions comprising an anti-PD-1 antibody or an anti-PD-L1 antibody. In some aspects, the pharmaceutical compositions are formulated for subcutaneous delivery. In some aspects, the pharmaceutical compositions further comprise an endoglycosidase hydrolase enzyme. Other aspects of the present disclosure are directed to methods of subcutaneously delivering a pharmaceutical composition comprising an anti-PD-1 antibody or an anti-PD-L1 antibody.

1 . A method of treating a subject in need thereof, comprising subcutaneously administering to the subject a dose of a pharmaceutical composition comprising (i) an antibody that specifically binds PD-1 or PD-L1 and inhibits the interaction of PD-1 and PD-L1 (“an anti-PD-1 antibody” or “an anti-PD-L1 antibody”, respectively) and (ii) an endoglycosidase hydrolase enzyme; wherein the dose comprises one or more subcutaneous unit doses; and wherein the dose comprises at least about 300 mg to at least about 2400 mg of the anti-PD-1 antibody or the anti-PD-L1 antibody. 
     
     
         2 . The method of  claim 1 , wherein;
 (i) the dose comprises two or more subcutaneous unit doses, and wherein the two or more subcutaneous unit doses are administered concurrently or subsequently;   (ii) the dose is administered about every one, two, three, four, six, or eight week: or   (iii) both (i) and (ii).   
     
     
         3 - 5 . (canceled) 
     
     
         6 . The method of  claim 1 , wherein;
 (i) the dose of the anti-PD-1 antibody or the anti-PD-L1 antibody is about 250 mg to about 600 mg administered about every week,   (ii) the dose of the anti-PD-1 antibody or the anti-PD-L1 antibody is about 300 mg to about 900 mg administered about every two weeks,   (iii) the dose of the anti-PD-1 antibody or the anti-PD-L1 antibody is about 900 mg to about 1500 mg administered about every four weeks, or   (iv) the dose of the anti-PD-L1 antibody is about 900 mg to about 1800 mg administered about every two weeks and   wherein the dose of the endoglycosidase hydrolase enzyme is at least about 1.000 units to at least about 30.000 units.   
     
     
         7 . (canceled) 
     
     
         8 . The method of  claim 1 , wherein;
 i. the dose of the anti-PD-1 antibody or the anti-PD-L1 antibody is about 300 mg administered about every week;   ii. the dose of the anti-PD-1 antibody or the anti-PD-L1 antibody is about 600 mg administered about every two weeks;   iii. the dose of the antibody or the anti-PD-L1 antibody is about 1200 mg administered about every four weeks: or   iv. the dose of the anti-PD-L1 antibody is about 1200 mg administered every two weeks.   
     
     
         9 . (canceled) 
     
     
         10 . The method of  claim 8 , wherein the dose of the antibody comprises:
 (i) a single subcutaneous unit dose of about 300 mg in a total administered volume of about 2 mL;   (ii) a single subcutaneous unit dose of about 1200 mg in a total administered volume of greater than about 5 mL;   (ii) two subcutaneous unit doses, wherein each of the two subcutaneous unit doses comprises about 300 mg of the antibody, and wherein at least one of the two subcutaneous unit doses comprises about 300 mg of the antibody in a total volume of greater than about 2 mL;   (iii) four subcutaneous unit doses, wherein each of the four subcutaneous unit doses comprises about 300 mg of the antibody, and wherein at least one of the four subcutaneous unit doses comprises about 300 mg of the antibody in a total volume of greater than 2 mL.   
     
     
         11 - 39 . (canceled) 
     
     
         40 . The method of  claim 1 , wherein the anti-PD-1 antibody or anti-PD-L1 antibody and the endoglycosidase hydrolase enzyme are administered at a dose of:
 i. about 300 mg of the antibody and about 4000 units of the endoglycosidase hydrolase enzyme, once about every week;   ii. about 600 mg of the antibody and about 8000 units of the endoglycosidase hydrolase enzyme, once about every two weeks: or   iii. about 1200 mg of the antibody and about 16.000 units of the endoglycosidase hydrolase enzyme, once about every four weeks.   
     
     
         41 - 50 . (canceled) 
     
     
         51 . The method of  claim 1 , wherein the endoglycosidase hydrolase enzyme cleaves hyaluronic acid at a hexosaminidic β (1-4) or (1-3) linkage. 
     
     
         52 . The method of  claim 1 , wherein the endoglycosidase hydrolase enzyme comprises;
 (i) a catalytic domain of hyaluronidase PH-20 (HuPH20), HYAL1, HYAL2, HYAL3, HYAL4, or HYALPS1;   (iii) an amino acid sequence having at least about 70% sequence identity to amino acids 36-490 of SEO ID NO: 1; or   (iii) both (i) and (ii)   
     
     
         53 - 54 . (canceled) 
     
     
         55 . The method of  claim 1 , wherein the endoglycosidase hydrolase enzyme comprises a hyaluronidase selected from:
 (i) HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, any variant, r any isoform thereof;   (iii) a modified hyaluronidase comprising one or more amino acid substitutions relative to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or a fragment thereof   (iii) rHuPH20 or a fragment thereof;   (iv) a modified rHuPH20, wherein the modified rHuPH20 comprises:
 a. one or more amino acid substitution in an alpha-helix region, a linker region, or both an alpha-helix region and a linker region relative to wild-type rHuPH20; 
 b. deletion of one or more N-terminal amino acid, one or more C-terminal amino acid, or one or more N-terminal amino acid and one or more C-terminal amino acid relative to wild-type rHuPH20; or 
 c. both (i) and (ii); and 
   (v) any combination of (i) to (iv).   
     
     
         56 - 61 . (canceled) 
     
     
         62 . The method of  claim 1 , wherein;
 (i) the anti-PD-1 antibody comprises an antibody selected from nivolumab, pembrolizumab, PDR001, MEDI-0680, cemiplimab, toripalimab, tislelizumab, INCSHR1210, TSR-042, GLS-010, AM-0001, STI-1110, AGEN2034, MGA012, BCD-100, IBI308, and any combination thereof; or   (ii) the anti-PD-L1 antibody comprises an antibody selected from BMS-936559, atezolizumab, durvalumab, avelumab, STI-1014, CX-072, KN035, LY3300054, BGB-A333, CK-301, and any combination thereof.   
     
     
         63 - 67 . (canceled) 
     
     
         68 . The method of claim  67 , wherein the subject is afflicted with a cancer selected from squamous cell carcinoma, small-cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), squamous NSCLC, nonsquamous NSCLC, glioma, gastrointestinal cancer, renal cancer, clear cell carcinoma, ovarian cancer, liver cancer, colorectal cancer, endometrial cancer, kidney cancer, renal cell carcinoma (RCC), prostate cancer, hormone refractory prostate adenocarcinoma, thyroid cancer, neuroblastoma, pancreatic cancer, glioblastoma, glioblastoma multiforme, cervical cancer, stomach cancer, bladder cancer, hepatoma, breast cancer, colon carcinoma, head and neck cancer, gastric cancer, germ cell tumor, pediatric sarcoma, sinonasal natural killer, melanoma, bone cancer, skin cancer, uterine cancer, cancer of the anal region, testicular cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, rectal cancer, solid tumors of childhood, cancer of the ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain cancer, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, environmentally-induced cancers including those induced by asbestos, virus-related cancers or cancers of viral origin (e.g., human papilloma virus (HPV-related or -originating tumors)), and any combination thereof. 
     
     
         69 . The method of  claim 1 , wherein the pharmaceutical composition is administered:
 (i) using an auto-injector or a wearable pump;   (ii) by subcutaneous infusion for less than about 10 minutes;   (iii) both (i) and (ii).   
     
     
         70 - 72 . (canceled) 
     
     
         73 . The method of  claim 1 , wherein the pharmaceutical composition further comprises:
 (i) at least two antioxidants selected from methionine, tryptophan, histidine, cysteine, ascorbic acid, glycine, DTPA, and EDTA;   (ii) a tonicity modifier and/or stabilizer selected from a sugar, an amino acid, a polyol, a salt, or a combination thereof;   (iii) a buffering agent selected from histidine, succinate, tromethamine, sodium phosphate, sodium acetate, and sodium citrate;   (iv) a surfactant selected from the group consisting of polysorbate 20, polysorbate 80, and poloxamer 188: or   (v) any combination of (i) to (iv).   
     
     
         74 - 75 . (canceled) 
     
     
         76 . The method of  claim 73 , wherein the pharmaceutical composition comprises:
 (i) at least about 1 to about 20 mM methionine;   (iii) at least about 10 μM to about 200 μM DTPA;   (iii) at least about 10 mM to at least about 500 mM sucrose;   (iv) at least about 5 mM to at least about 100 mM histidine;   (v) at least about 0.01% w/v to at least about 0.1% w/v polysorbate 80; or   (vi) any combination of (i) to (v).   
     
     
         77 . (canceled) 
     
     
         78 . The method of  claim 73 , wherein the pharmaceutical composition comprises:
 (i) about 5 mM methionine;   (ii) about 50 μM DTPA;   (iii) about 250 mM sucrose;   (iv) about 20 mM histidine;   (v) about 0.05% w/v polysorbate 80: or   (vi) any combination of (i) to (v).   
     
     
         79 - 100 . (canceled) 
     
     
         101 . The method of  claim 1 , wherein the pharmaceutical composition comprises:
 (i) (a) about 120 mg/mL of the anti-PD-1 antibody,
 (b) about 20 mM L-histidine, 
 (c) about 250 mM sucrose, 
 (d) about 0.05% w/v polysorbate 80, 
 (e) about 50 μM pentetic acid, 
 (f) about 5 mM methionine, and 
 (g) about 0.0182 mg/mL rHuPH20; 
   (ii) (a) about 120 mg/mL of the anti-PD-1 antibody,
 (b) about 20 mM L-histidine, 
 (c) about 250 mM sucrose, 
 (d) about 0.05% w/v polysorbate 80, 
 (e) about 50 μM pentetic acid, 
 (f) about 5 mM methionine, and 
 (g) about 2000 U/mL rHuPH20; 
   (iii) (a) about 150 mg/mL of the anti-PD-1 antibody,
 (b) about 20 mM L-histidine, 
 (c) about 250 mM sucrose, 
 (d) about 0.05% w/v polysorbate 80, 
 (e) about 50 uM pentetic acid, 
 (f) about 5 mM methionine, and 
 (g) about 0.0182 mg/mL rHuPH20; or 
   (i) (a) about 150 mg/mL of the anti-PD-1 antibody,
 (b) about 20 mM L-histidine, 
 (c) about 250 mM sucrose, 
 (d) about 0.05% w/v polysorbate 80, 
 (e) about 50 μM pentetic acid, 
 (f) about 5 mM methionine, and 
 (g) about 2000 U/mL rHuPH20. 
   
     
     
         102 - 104 . (canceled) 
     
     
         105 . The method of  claim 101 , wherein the pharmaceutical composition comprises a pH of about 5.2 to about 6.8. 
     
     
         106 - 163 . (canceled) 
     
     
         164 . The pharmaceutical composition of  claim 1 , further comprising a second therapeutic agent wherein the second therapeutic agent is a checkpoint inhibitor selected from the group consisting of an anti-CTLA-4 antibody, an anti-LAG-3 antibody, an anti-TIM3 antibody, an anti-TIGIT antibody, an anti-TIM3 antibody, an anti-NKG2a antibody, an anti-OX40 antibody, an anti-ICOS antibody, an anti-MICA antibody, an anti-CD137 antibody, an anti-KIR antibody, an anti-TGF antibody, an anti-IL-10 antibody, an anti-IL-8 antibody, an anti-B7-H4 antibody, an anti-Fas ligand antibody, an anti-CXCR4 antibody, an anti-mesothelin antibody, an anti-CD27 antibody, an anti-GITR, or any combination thereof. 
     
     
         165 - 168 . (canceled) 
     
     
         169 . A unit dose comprising:
 (i) (a) about 120 mg/mL of the anti-PD-1 antibody;
 (b) about 20 mM L-histidine 
 (c) about 250 mM sucrose 
 (d) about 0.05% w/v polysorbate 80 
 (e) about 50 μM pentetic acid 
 (f) about 5 mM methionine and 
 (g) about 2000 U/mL rHuPH20; or 
   (ii) (a) about 150 mg/mL of the anti-PD-1 or anti-PD-L1 antibody,
 (b) about 20 mM L-histidine, 
 (c) about 250 mM sucrose, 
 (d) about 0.05% w/v polysorbate 80, 
 (e) about 50 μM pentetic acid, 
 (f) about 5 mM methionine, and 
 (g) about 2000 U/mL rHuPH20. 
   
     
     
         170 . (canceled) 
     
     
         171 . A vial, an autoinjector, or a wearable pump comprising  claim 169 . 
     
     
         172 - 175 . (canceled)