Subcutaneous Formulations Of Anti-CD38 Antibodies And Their Uses

Abstract

The present invention relates to subcutaneous formulations of anti-CD38 antibodies and their uses.

1 . A pharmaceutical composition comprising about 1,800 mg of an anti-CD38 antibody and about 30,000 U of a hyaluronidase, wherein the anti-CD38 antibody is of an IgG1 isotype and comprises a heavy chain variable region sequence of SEQ ID NO: 4 and a light chain variable region sequence of SEQ ID NO: 5, and wherein the hyaluronidase is rHuPH20 (SEQ ID NO: 22). 
     
     
         2 . The pharmaceutical composition of  claim 1 , further comprising a pharmaceutically acceptable carrier. 
     
     
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         14 . The pharmaceutical composition of  claim 2 , wherein the anti-CD38 antibody comprises
 a heavy chain of SEQ ID NO: 12 and a light chain of SEQ ID NO: 13.   
     
     
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         25 . The pharmaceutical composition of  claim 2 , further comprising
 a) from about 5 mM to about 50 mM histidine; and   b) from about 50 mM to about 400 mM sorbitol.   
     
     
         26 . The pharmaceutical composition of  claim 25 , further comprising
 a) from about 0.01% w/v to about 0.1% polysorbate-20 (PS-20);   b) from about 0.1 mg/mL to about 2.5 mg/mL methionine; or   c) from about 0.01% w/v to about 0.1% PS-20 and from about 0.1 mg/mL to about 2.5 mg/mL methionine.   
     
     
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         28 . The pharmaceutical composition of  claim 25 , comprising
 a)   a) about 10 mM histidine; and   b) from about 100 mM to about 300 mM sorbitol.   
     
     
         29 . The pharmaceutical composition of  claim 28 , further comprising
 a) from about 0.01% w/v to about 0.04% w/v PS-20; and   b) from about 1 mg/mL to about 2 mg/mL methionine.   
     
     
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         31 . The pharmaceutical composition of  claim 26 , comprising
 a)   a) about 10 mM histidine;   b) about 300 mM sorbitol;   c) about 0.04% w/v PS-20; and   d) about 1 mg/mL methionine; pH about 5.6.   
     
     
         32 . The pharmaceutical composition of  claim 26 , comprising
 a)   b)
 a) about 10 mM histidine; 
 b) about 300 mM sorbitol; 
 c) about 0.04% w/v PS-20; and 
 d) about 2 mg/mL methionine; pH about 5.5. 
   
     
     
         33 . The pharmaceutical composition of  claim 26 , comprising
 a)   b)
 a) about 10 mM histidine; 
 b) about 300 mM sorbitol; 
 c) about 0.01% w/v PS-20; and 
 d) about 2 mg/mL methionine; pH about 5.5. 
   
     
     
         34 . The pharmaceutical composition of  claim 26 , comprising
 a) about 10 mM histidine;   b) about 300 mM sorbitol;   c) about 0.02% w/v PS-20; and   d) about 2 mg/mL methionine; pH about 5.5.   
     
     
         35 . The pharmaceutical composition of  claim 26 , comprising
 a) about 10 mM histidine;   b) about 300 mM sorbitol;   c) about 0.06% w/v PS-20; and   d) about 2 mg/mL methionine; pH about 5.5.   
     
     
         36 . The pharmaceutical composition of  claim 26 , comprising
 a) about 10 mM histidine;   b) about 300 mM sorbitol;   c) about 0.04% w/v PS-20; and   d) about 1 mg/mL methionine; pH about 5.5.   
     
     
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         41 . The pharmaceutical composition of  claim 2  which is in a dosage unit form. 
     
     
         42 . A method of treating a CD38-positive multiple myeloma (MM) in a subject, comprising administering subcutaneously to the subject in need thereof a pharmaceutical composition comprising about 1,800 mg of an anti-CD38 antibody and about 30,000 U of a hyaluronidase for a time sufficient to treat the CD38-positive MM, wherein the anti-CD38 antibody is of an IgG1 isotype and comprises a heavy chain variable region sequence of SEQ ID NO: 4 and a light chain variable region sequence of SEQ ID NO: 5, and wherein the hyaluronidase is rHuPH20 (SEQ ID NO: 22). 
     
     
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         44 . The method of  claim 42 , wherein the anti-CD38 antibody comprises a heavy chain sequence of SEQ ID NO: 12 and a light chain sequence of SEQ ID NO: 13. 
     
     
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         59 . The method of  claim 42 , wherein the pharmaceutical composition further comprises, from about 5 mM to about 50 mM histidine and from about 50 mM to about 400 mM sorbitol, optionally further comprising from about 0.01% w/v to about 0.1% w/v polysorbate-20 (PS-20), from about 0.1 mg/mL to about 2.5 mg/mL methionine, or from about 0.01% w/v to about 0.1% w/v PS-20 and/or from about 0.1 mg/mL to about 2.5 mg/mL methionine. 
     
     
         60 . The method of  claim 59 , wherein the pharmaceutical composition comprises, about 10 mM histidine and from about 100 mM to about 300 mM sorbitol, optionally further comprising from about 0.01% w/v to about 0.04% w/v PS-20, from about 1 mg/mL to about 2 mg/mL methionine, or from about 0.01% w/v to about 0.04% w/v PS-20 and from about 1 mg/mL to about 2 mg/mL methionine. 
     
     
         61 . The method of  claim 60 , wherein the pharmaceutical composition comprises about 10 mM histidine, about 300 mM sorbitol, about 0.04% w/v PS-20 and about 1 mg/mL methionine; pH about 5.6. 
     
     
         62 . The method of  claim 60 , wherein the pharmaceutical composition comprises about 10 mM histidine, about 300 mM sorbitol, about 0.04% w/v PS-20 and about 2 mg/mL methionine; pH about 5.5. 
     
     
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         68 . The method of  claim 42 , further administering a second therapeutic agent. 
     
     
         69 . The method of  claim 68 , wherein the second therapeutic agent is a proteasome inhibitor, an alkylating agent or a glutamic acid derivative, or combinations thereof. 
     
     
         70 . The method of  claim 69 , wherein
 a) the proteasome inhibitor is bortezomib, carfilzomib or ixazomib;   b) the alkylating agent is busulfan, cyclophosphamide, bendamustine, chlorambucli, carboplatin, cisplatin, temozolomide, melphalan, carmustine, lomustine, dacarbazine, oxaliplatin, ifosfamide, mechlorethamine, thiotepa, trabectedin or streptozocin; and   c) the glutamic acid derivative is lenalidomide, thalidomide or pomalidomide.   
     
     
         71 . The method of  claim 70 , further comprising administering a corticosteroid. 
     
     
         72 . The method of  claim 71 , wherein the corticosteroid is dexamethasone or prednisone. 
     
     
         73 . The method of  claim 72 , wherein the corticosteroid is dexamethasone. 
     
     
         74 . A unit dosage form, comprising
 a) an anti-CD38 antibody of an IgG1 isotype comprising a heavy chain variable region sequence of SEQ ID NO: 4 and a light chain variable region sequence of SEQ ID NO: 5 in an amount of about 1,800 mg;   b) a hyaluronidase in an amount of about 30,000 U;   c) histidine at a concentration of from about 5 mM to about 15 mM;   d) sorbitol at a concentration of from about 100 mM to about 300 mM;   e) polysorbate-20 (PS-20) at a concentration of from about 0.01% w/v to about 0.04% w/v; and   f) methionine at a concentration of from about 1 mg/mL to about 2 mg/mL, at a pH of about 5.5; wherein the hyaluronidase is rHuPH20 (SEQ ID NO: 22).   
     
     
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         77 . The unit dosage form of  claim 74 , wherein histidine is present at a concentration of about 10 mM. 
     
     
         78 . The unit dosage form of  claim 77 , wherein sorbitol is present at a concentration of about 300 mM. 
     
     
         79 . The unit dosage form of  claim 78 , wherein polysorbate is present at a concentration of about 0.04% w/v. 
     
     
         80 . The unit dosage form of  claim 79 , wherein methionine is present at a concentration of about 1 mg/mL. 
     
     
         81 . The unit dosage form of  claim 80 , optionally comprising sucrose at a concentration of from about 100 mM to about 200 mM. 
     
     
         82 . The unit dosage form of  claim 81 , wherein the anti-CD38 antibody comprises a heavy chain sequence of SEQ ID NO: 12 and a light chain sequence of SEQ ID NO: 13. 
     
     
         83 . A container comprising the unit dosage form of  claim 82 . 
     
     
         84 . A unit dosage form, comprising
 a) an anti-CD38 antibody of an IgG1 isotype comprising a heavy chain variable region sequence of SEQ ID NO: 4 and a light chain variable region sequence of SEQ ID NO: 5 in an amount of about 1,800 mg;   b) a hyaluronidase in an amount of about 30,000 U;   c) histidine at a concentration of about 10 mM;   d) sorbitol at a concentration of about 300 mM;   e) polysorbate-20 (PS-20) at a concentration of about 0.04% w/v; and   f) methionine at a concentration of about 1 mg/mL, at a pH of about 5.6; wherein the hyaluronidase is rHuPH20 (SEQ ID NO: 22).   
     
     
         85 . A container comprising the unit dosage form of  claim 84 . 
     
     
         86 . The unit dosage form of  claim 84 , wherein the anti-CD38 antibody comprises a heavy chain sequence of SEQ ID NO: 12 and a light chain sequence of SEQ ID NO: 13.