Combination therapy with a hyaluronan-degrading enzyme and an immune checkpoint inhibitor

Abstract

Provided are methods of treatment of cancers with combinations of and compositions containing a soluble hyaluronidase, such as a polymer-modified soluble hyaluronidase, and an immune checkpoint inhibitor for treating cancers, including solid and non-solid tumors. The combinations and compositions also are provided.

What is claimed: 
     
         1 . A method for treating a cancer, comprising:
 intravenously administering a first composition comprising a soluble hyaluronidase, wherein the hyaluronidase is conjugated to a polymer or is formulated for slow release or is encoded in a viral vector; and   then, within 8 to 48 hours after administering the hyaluronidase, intravenously administering a second composition comprising an immune checkpoint inhibitor.   
     
     
         2 . The method of  claim 1 , wherein the hyaluronidase is conjugated to a polymer. 
     
     
         3 . The method of  claim 1 , wherein:
 the cancer comprises a tumor that expresses hyaluronan; and   the hyaluronidase is conjugated to a polymer.   
     
     
         4 . The method of  claim 1 , wherein the hyaluronidase is administered separately from, and at least 12 hours up to 48 hours before the immune checkpoint inhibitor; wherein the immune checkpoint inhibitor is an immune checkpoint inhibitor antibody or an antigen binding fragment thereof. 
     
     
         5 . The method of  claim 1 , wherein the immune checkpoint inhibitor is an immune checkpoint inhibitor antibody or antigen binding fragment thereof that is an anti-CTLA-4, anti-PD-1, or anti-PD-L1 antibody, or comprises an antigen binding fragment of the anti-CTLA-4, anti-PD-1, or anti-PD-L1 antibody. 
     
     
         6 . The method of  claim 2 , wherein the polymer-conjugated soluble hyaluronidase is a PEGylated soluble PH20 hyaluronidase. 
     
     
         7 . The method of  claim 2 , wherein the hyaluronidase is a human hyaluronidase. 
     
     
         8 . The method of  claim 1 , wherein the cancer comprises a solid tumor. 
     
     
         9 . The method of  claim 1 , wherein the cancer is selected from among pancreatic cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, mesothelioma, non-small cell lung cancer (NSCLC), and colon cancer. 
     
     
         10 . The method of  claim 1 , wherein the soluble hyaluronidase is a human PH20. 
     
     
         11 . The method of  claim 10 , wherein:
 the soluble hyaluronidase is a soluble PH20 hyaluronidase;   the soluble hyaluronidase is conjugated to a polymer;   the polymer is PEG; and   the PEGylated soluble PH20 hyaluronidase is a C-terminal truncated human PH20 selected from among:
 a) a contiguous sequence of amino acids in SEQ ID NO: 217 that contains amino acid residues 36-464 of SEQ ID NO: 217, and residues up to a C-terminal amino acid residue, whereby the polypeptide is C-terminally truncated so that it does not include the full-length of the polypeptide whose sequence is set forth as amino acids 1-509 or 36-509 of SEQ ID NO: 217; and 
 b) a sequence of amino acids that has at least about 95%, 96%, 97%, 98%, or 99% sequence identity to a sequence of amino acids of a) that is soluble and retains hyaluronidase activity. 
   
     
     
         12 . The method of  claim 11 , wherein the soluble hyaluronidase in the PEGylated soluble PH20 hyaluronidase comprises the sequence of amino acids set forth in any of SEQ ID NOs: 123-158, or a sequence of amino acids that exhibits at least 95% sequence identity to a sequence of amino acids set forth in any of SEQ ID NOs: 123-158 and retains hyaluronidase activity. 
     
     
         13 . The method of  claim 12 , wherein the PEG is methoxypolyethylene glycol (mPEG). 
     
     
         14 . The method of  claim 1 , wherein the immune checkpoint inhibitor is an immune checkpoint inhibitor antibody or antigen binding fragment thereof that is a monoclonal antibody or antigen binding fragment thereof. 
     
     
         15 . The method of  claim 1 , wherein the immune checkpoint inhibitor is an immune checkpoint inhibitor antibody or antigen binding fragment thereof that is an anti-CTLA-4 antibody or antigen binding fragment thereof. 
     
     
         16 . The method of  claim 15 , wherein the anti-CTLA-4 antibody or antigen-binding fragment thereof is selected from among:
 a) Ipilimumab, a derivative thereof, or an antigen-binding fragment thereof, comprising:   a heavy chain variable domain consisting of the sequence of amino acids set forth in SEQ ID NO: 22 and a light chain variable domain consisting of the sequence of amino acids set forth in SEQ ID NO: 24; or   a variable heavy chain consisting of a sequence of amino acids that has a sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% to the heavy chain set forth in SEQ ID NO: 22 and a variable light chain consisting of a sequence of amino acids that has a sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% to the light chain set forth in SEQ ID NO: 24; and   b) Tremelimumab, a derivative thereof, or an antigen-binding fragment thereof, comprising:   a heavy chain variable domain consisting of the sequence of amino acids set forth in SEQ ID NO: 34 and a light chain variable domain consisting of the sequence of amino acids set forth in SEQ ID NO: 36; or   a variable heavy chain consisting of a sequence of amino acids that has a sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% to the heavy chain set forth in SEQ ID NO: 34 and a variable light chain consisting of a sequence of amino acids that has a sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% to the light chain set forth in SEQ ID NO: 36.   
     
     
         17 . The method of  claim 1 , wherein the immune checkpoint inhibitor is an immune checkpoint inhibitor antibody or antigen binding fragment that is an anti-PD-1 antibody or antigen binding fragment thereof. 
     
     
         18 . The method of  claim 1 , wherein the immune checkpoint inhibitor is an immune checkpoint inhibitor antibody or antigen binding fragment that is an anti-PD-1 antibody or antigen-binding fragment thereof, selected from among:
 a) Nivolumab, or an antigen-binding fragment thereof, comprising:   a heavy chain variable domain consisting of the sequence of amino acids set forth in SEQ ID NO: 54 and a light chain variable domain consisting of the sequence of amino acids set forth in SEQ ID NO: 56; or   a variable heavy chain consisting of a sequence of amino acids that has a sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% to the heavy chain set forth in SEQ ID NO: 54 and a variable light chain consisting of a sequence of amino acids that has a sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% to the light chain set forth in SEQ ID NO: 56;   b) MK-3475, or an antigen-binding fragment thereof, comprising:   a heavy chain variable domain consisting of the sequence of amino acids set forth in SEQ ID NO: 68 and a light chain variable domain consisting of the sequence of amino acids set forth in SEQ ID NO: 70; or   a variable heavy chain consisting of a sequence of amino acids that has a sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% to the heavy chain set forth in SEQ ID NO: 68 and a variable light chain consisting of a sequence of amino acids that has a sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% to the light chain set forth in SEQ ID NO: 70; and   c) Pidilizumab, or an antigen-binding fragment thereof, comprising:   a heavy chain variable domain consisting of the sequence of amino acids set forth in SEQ ID NO: 82 and a light chain variable domain consisting of the sequence of amino acids set forth in SEQ ID NO: 84; or   a variable heavy chain consisting of a sequence of amino acids that has a sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% to the heavy chain set forth in SEQ ID NO: 82 and a variable light chain consisting of a sequence of amino acids that has a sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% to the light chain set forth in SEQ ID NO: 84.   
     
     
         19 . The method of  claim 1 , wherein the immune checkpoint inhibitor is an immune checkpoint inhibitor antibody or antigen binding fragment thereof that is an anti-PD-L1 antibody or antigen-binding fragment thereof. 
     
     
         20 . The method of  claim 19 , wherein the anti-PD-L1 antibody or antigen-binding fragment thereof is selected from among:
 a) BMS-936559, or an antigen-binding fragment thereof, comprising:   a heavy chain variable domain consisting of the sequence of amino acids set forth in SEQ ID NO: 92 and a light chain variable domain consisting of the sequence of amino acids set forth in SEQ ID NO: 94; or   a variable heavy chain consisting of a sequence of amino acids that has a sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% to the heavy chain set forth in SEQ ID NO: 92 and a variable light chain consisting of a sequence of amino acids that has a sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% to the light chain set forth in SEQ ID NO: 94;   b) MEDI4736, or an antigen-binding fragment thereof, comprising:   a heavy chain variable domain consisting of the sequence of amino acids set forth in SEQ ID NO: 102 and a light chain variable domain consisting of the sequence of amino acids set forth in SEQ ID NO: 104; or   a variable heavy chain consisting of a sequence of amino acids that has a sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% to the heavy chain set forth in SEQ ID NO: 102 and a variable light chain consisting of a sequence of amino acids that has a sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% to the light chain set forth in SEQ ID NO: 104; and   c) MPDL3280A, or an antigen-binding fragment thereof, comprising:   a heavy chain variable domain consisting of the sequence of amino acids set forth in SEQ ID NO: 114 and a light chain variable domain consisting of the sequence of amino acids set forth in SEQ ID NO: 115; or   a variable heavy chain consisting of a sequence of amino acids that has a sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% to the heavy chain set forth in SEQ ID NO: 114 and a variable light chain consisting of a sequence of amino acids that has a sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% to the light chain set forth in SEQ ID NO: 115.   
     
     
         21 . The method of  claim 7 , wherein:
 the cancer comprises a solid tumor;   the solid tumor comprises a moderate to high hyaluronan (HA) solid tumor;   the amount of HA is high if the amount is at least or at least about 2.5-fold higher than the amount or level of HA in a corresponding normal, control or healthy tissue; and   the amount of HA is moderate if the amount is at about 1.3-fold to 2-fold or higher than the amount or level of HA in a corresponding normal, control or healthy tissue.   
     
     
         22 . The method of  claim 1 , wherein:
 the soluble hyaluronidase is a PH20;   the polymer is a PEG; and   the soluble hyaluronidase in the PEGylated soluble PH20 hyaluronidase is a human PH20 that lacks a C-terminal glycosylphosphatidylinositol (GPI) attachment site or a portion of the GPI attachment site, whereby the PH20 is soluble.   
     
     
         23 . The method of  claim 1 , wherein:
 the soluble hyaluronidase is a PH20;   the polymer is a PEG; and   the hyaluronidase in the PEGylated soluble PH20 hyaluronidase comprises a sequence of amino acids set forth in any of SEQ ID NOS: 123-158, or a sequence of amino acids that exhibits at least 98% sequence identity to a sequence of amino acids set forth in any of SEQ ID NOs: 123-158 and retains hyaluronidase activity.   
     
     
         24 . The method of  claim 23 , wherein the primary sequence of the soluble PH20 hyaluronidase in the PEGylated soluble PH20 hyaluronidase consists of sequence of amino acids set forth in SEQ ID NO:123. 
     
     
         25 . The method of  claim 1 , comprising administering a corticosteroid. 
     
     
         26 . The method of  claim 25 , wherein the corticosteroid is a glucocorticoid. 
     
     
         27 . The method of  claim 26 , wherein the glucocorticoid is selected from among cortisones, dexamethasones, hydrocortisones, methylprednisolones, prednisolones, and prednisones. 
     
     
         28 . The method of  claim 25 , wherein the corticosteroid is administered prior to, concurrent with, intermittently with or subsequent to administration of the hyaluronidase. 
     
     
         29 . A combination, comprising:
 a first composition comprising a soluble hyaluronidase, wherein the hyaluronidase is conjugated to a polymer or is formulated for slow release or is encoded in a vector for delivery to a tumor; and   a second composition comprising an immune checkpoint inhibitor.   
     
     
         30 . The combination of  claim 29 , wherein:
 the hyaluronidase is conjugated to a polymer; and   the hyaluronidase is a PH20 that is a human PH20.   
     
     
         31 . The combination of  claim 30 , wherein:
 the PH20 is a C-terminal truncated PH20 selected from among:   a) a contiguous sequence of amino acids in SEQ ID NO: 217 that contains amino acids 36-464 of SEQ ID NO: 217 and residues up to a C-terminal amino acid residue, whereby the polypeptide is C-terminally truncated so that it does not include the full-length of the polypeptide whose sequence is set forth as amino acids 1-509 or 36-509 of SEQ ID NO: 217; and   b) a sequence of amino acids that has at least 85% sequence identity to the sequence of amino acids of a) that is soluble and retains hyaluronidase activity.   
     
     
         32 . The combination of  claim 30 , wherein the PH20 comprises a sequence of amino acids set forth in any of SEQ ID NOs: 123-158, or a sequence of amino acids that exhibits at least 85% sequence identity to a sequence of amino acids set forth in any of SEQ ID NOs: 123-158 and retains hyaluronidase activity.