Compositions and methods for treating or ameliorating fibrosis, systemic sclerosis, scleroderma and graft versus host disease

Abstract

Provided are Adenosine Deaminase (ADA), or a polypeptides or peptides having an ADA activity, or an ADA conjugate, pharmaceutical compositions and formulations, products of manufacture and kits, and methods containing them for the prevention and treatment of a scleroderma-associated vasculopathy, in particular proliferative obliterative vasculopathy, progressive obliterative vasculopathy or an idiopathic obliterative vasculopathy and/or preventing or decreasing the progression of scleroderma, wherein optionally the scleroderma comprises a local scleroderma or a diffuse, or a systemic scleroderma.

1 - 20 . (canceled) 
     
     
         21 . A therapeutic combination comprising:
 (a) an agent, a compound or a composition having an Adenosine Deaminase (ADA) enzyme activity, or is capable of increasing or sustaining levels of Adenosine Deaminase enzyme activity; and   (b) one or more of a therapeutic agent or agents selected from the group consisting of:
 (i) a calcium channel blocker for Raynaud's syndrome; 
 (ii) an antihistamine for pruritus; 
 (iii) an H2 blocker or proton pump inhibitor for an esophageal symptom; 
 (iv) and anti-diarrheal agent or an anti-spasmotic for a lower GI symptom; 
 (v) an ADEI/ARB medication for hypertension or other renal manifestations of systemic sclerosis; 
 (vi) an immunosuppressive agents combining such agents as methotrexate, cyclophosphamide, mycophenolate mofetil, or rituximab; 
 (vii) an antibiotic; 
 (viii) a cytokine; 
 (ix) an immunoregulatory agent; 
 (x) an anti-inflammatory agents; 
 (xi) a complement activating agent; 
   (xii) a carbohydrate-binding domain; and   (xiii) any combination of (i) to (xii).   
     
     
         22 . The therapeutic combination  claim 21 , wherein the agent, compound or composition comprises or is: (i) an Adenosine Deaminase enzyme; (ii) a polypeptide or a peptide having an Adenosine Deaminase activity; or, (iii) a conjugate of (i) or (ii). 
     
     
         23 . The therapeutic combination  claim 21 , wherein the agent, compound or composition comprises: a recombinant, an isolated, a synthetic, extracted or a peptidomimetic version of the agent, compound or composition having an Adenosine Deaminase enzyme activity or is capable of increasing or sustaining levels of adenosine deaminase enzyme activity; or, a polypeptide or peptide having Adenosine Deaminase activity. 
     
     
         24 . The therapeutic combination  claim 23 , wherein the Adenosine Deaminase enzyme, or the polypeptide or peptide having Adenosine Deaminase activity, is or is derived from an animal source, wherein optionally the animal source is a mammal, wherein optionally the mammal is a human, a bovine or a mixture thereof. 
     
     
         25 . The therapeutic combination  claim 21 , wherein the agent, compound or composition is:
 (a) manufactured as or is formulated in a polyethylene glycol conjugate form, or is administered in a polyethylene glycol conjugate form, wherein optionally the polyethylene glycol conjugate form is a PEGylated bovine adenosine deaminase enzyme, which optionally comprises pegademase, or elapegademase, or a poly(oxy-1,2-ethanediyl), α-carboxy-ω-methoxy-amide with an Adenosine Deaminase enzyme activity or polypeptide having Adenosine Deaminase enzyme activity, or   (b) conjugated to, linked to or covalently linked to a non-antigenic polymer, wherein optionally the non-antigenic polymer comprises a polyalkylene oxide, dextran, polyvinyl pyrrolidones, polysaccharides, starches, polyvinyl alcohols, polyacryl amides; or   (c) conjugated to, linked to or covalently linked to a substantially hydrolysis-resistant urethane bond between the epsilon amino groups of enzymes and a functionalized terminal group,   wherein optionally an Adenosine Deaminase enzyme, or a polypeptide or a peptide having an Adenosine Deaminase enzyme activity, is conjugated through epsilon amino group modifications of lysines, or modifications of carboxylic acid groups.   
     
     
         26 . The therapeutic combination  claim 25 , wherein the Adenosine Deaminase (ADA) enzyme, or a conjugate of the polypeptide or peptide having an Adenosine Deaminase (ADA) enzyme activity, comprises from between about 1 to about 25 polymeric strands attached to each molecule of the ADA, or the polypeptide or peptide having an ADA activity. 
     
     
         27 . The therapeutic combination  claim 25 , wherein the Adenosine Deaminase enzyme, or the polypeptide or peptide having Adenosine Deaminase enzyme activity, is conjugated to a polyalkylene oxide, wherein optionally the polyalkylene oxide is a polyethylene glycol (PEG),
 wherein optionally the polyalkylene oxide is a straight, branched or multi-arm polymer, and   optionally the polyalkylene oxide or PEG has a molecular weight (MW) ranging from between about 2,000 to about 45,000 daltons.   
     
     
         28 . The therapeutic combination  claim 25 , wherein the Adenosine Deaminase enzyme, or the polypeptide or peptide having Adenosine Deaminase enzyme activity, is conjugated with either of: 
       
         
           
           
               
               
           
         
         wherein n is a positive integer between 1 and about 5,000. 
       
     
     
         29 . The therapeutic combination  claim 25 , wherein the Adenosine Deaminase enzyme, or the polypeptide or peptide having an Adenosine Deaminase enzyme activity, is a conjugate of formula:
   [R—NH] z -(ADA)
   where z is a positive integer from about 1 to about 80; and R comprises a substantially non-antigenic polymer,   and optionally the substantially non-antigenic polymer is in a releasable or non-releasable form,   and optionally the substantially non-antigenic polymer is a linear, branched or a multi-armed polyalkylene oxide, wherein optionally the polyalkylene oxide is a polyethylene glycol (PEG), having average MW from between about 1000 to about 100,000 Da.   
     
     
         30 . The therapeutic combination  claim 29 , wherein the polyalkylene oxide is functionalized as:
   —C(═Y 74 )—(CH 2 ) m —(CH 2 CH 2 O) n —,
     —C(═Y 74 )—Y—(CH 2 ) m —(CH 2 CH 2 O) n —,
     —C(═Y 74 )—NR 11 —(CH 2 ) m —(CH 2 CH 2 O) n —,
     —CR 75 R 76 —(CH 2 ) m —(CH 2 CH 2 O) n —,
   where R 11 , R 75  and R 76  are independently selected from among H, C 1-6 alkyls, aryls, substituted aryls, aralkyls, heteroalkyls, substituted heteroalkyls and substituted C 1-6  alkyls; m is zero or is a positive integer; Y 74  is O or S; and n represents the degree of polymerization.   
     
     
         31 . The therapeutic combination  claim 21 , wherein the agent, compound or composition, or the one or more of a therapeutic agent or agents, is formulated as a pharmaceutical composition. 
     
     
         32 . The therapeutic combination  claim 21 , wherein the agent, compound or composition, or the one or more of a therapeutic agent or agents, is formulated for enteral or parenteral administration; or, is formulated for administration by oral, nasal, rectal, intravaginal, topical, subcutaneous, intradermal, intramuscular (IM), intravenous (IV) or intrathecal (IT) intracerebral, epidural, intracranial or rectal route; or, is formulated for administration by inhalation or spray. 
     
     
         33 . The therapeutic combination  claim 21 , wherein the agent, compound or composition, or the one or more of a therapeutic agent or agents, is formulated for: oral, rectal, intravaginal, topical, subcutaneous, intradermal, intramuscular (IM), intravenous (IV) or intrathecal (IT) intracerebral, epidural, intracranial or rectal, nasal, or by inhalation or spray, administration. 
     
     
         34 . The therapeutic combination  claim 21 , wherein the agent, compound or composition, or the one or more of a therapeutic agent or agents, is contained in, or is carried in, or is in the form of:
 (a) a nanoparticle, a particle, a micelle, a liposome, a lipoplex, a polymersome, a polyplex, a dendrimer, a nanolipoparticle, a vesicle or a liposomal membrane,   wherein optionally the nanoparticle, particle, micelle, liposome, lipoplex, polymersome, polyplex, dendrimer, nanolipoparticle, vesicle or liposomal membrane is designed to target a specific molecule, wherein optionally the specific molecule is a biologic molecule,   and optionally the nanoparticle, particle, micelle, liposome, lipoplex, polymersome, polyplex, dendrimer, nanolipoparticle, vesicle or liposomal membrane comprises a cell surface targeting compound for targeting a particular cell, wherein optionally the particular cell is a vascular cell, a fibroblast, a myocyte or heart cell or an endothelial cell, and optionally the targeting compound is a targeting polypeptide capable of specifically binding to the cell; or   (b) a tablet, a pill, a capsule, a gel, a geltab, a liquid, a powder, an emulsion, a lotion, an aerosol, a spray, a lozenge, an aqueous or a sterile or an injectable solution, or an implant.