Claims for Patent: 10,391,154

Summary for Patent: 10,391,154

Title:	Compositions and methods for treating or ameliorating fibrosis, systemic sclerosis and scleroderma
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.
Inventor(s):	Schreiber; Brian Dean (Oshkosh, WI), Fornasini; Gianfranco (Bethesda, MD), Soukhareva; Nadejda (Derwood, MD), Ramamurthy; Santosh Kumar (Columbia, MD)
Assignee:	LEADIANT BIOSCIENCES LTD. (London, GB)
Application Number:	16/037,795
Patent Claims:	1. A method for arresting, treating, ameliorating or preventing scleroderma-associated vasculopathies and vascular changes, or preventing or decreasing progression of scleroderma in an individual in need thereof, comprising: (a) (i) providing or having provided an Adenosine Deaminase (ADA) enzyme or a composition comprising an Adenosine Deaminase (ADA) enzyme; and (ii) administering or having administered an effective amount of the ADA enzyme or composition to the individual in need thereof; or (b) administering an effective amount of an Adenosine Deaminase (ADA) enzyme or a composition comprising an Adenosine Deaminase (ADA) enzyme to the individual in need thereof. 2. The method of claim 1, wherein the scleroderma-associated vasculopathy is a proliferative obliterative vasculopathy, wherein optionally the proliferative obliterative vasculopathy is an idiopathic obliterative vasculopathy or a progressive obliterative vasculopathy, Raynaud's syndrome, edematous puffy hands, telangiectasias, digital ulcers, pulmonary arterial hypertension (PAH), myocardial dysfunction, scleroderma renal crisis, vascular wall thickening, vascular occlusion, vascular thromboses or a destructive vasculopathy, wherein optionally the Raynaud's syndrome is associated with scleroderma, nonpitting edema of the hands, distal finger ulcers and/or facial or peri-oral skin tightening with decreased oral aperture, wherein the Raynaud's syndrome, nonpitting edema of the hands, distal finger ulcers and/or facial or peri-oral skin tightening are early pathological expressions of scleroderma. 3. The method of claim 1, wherein the scleroderma comprises a local or focal scleroderma or a diffuse, or a systemic scleroderma, or a focal or systemic sclerosis. 4. The method of claim 1, wherein the Adenosine Deaminase enzyme is 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. 5. The method of claim 1, wherein the ADA enzyme is a recombinant ADA enzyme, an isolated or extracted ADA enzyme, a synthetic ADA enzyme, or a peptidomimetic version of the ADA enzyme. 6. The method of claim 5, wherein the Adenosine Deaminase enzyme 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. 7. The method of claim 1, wherein the ADA enzyme 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: a pegademase; an elapegademase; a poly(oxy-1,2-ethanediyl), or an .alpha.-carboxy-.omega.-methoxy-amide, or (b) 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 the Adenosine Deaminase enzyme is conjugated through epsilon amino group modifications of lysines, or modifications of carboxylic acid groups. 8. The method of claim 4, wherein the ADA enzyme comprises from between about 1 to about 25 polymeric strands. 9. The method of claim 4, wherein the Adenosine Deaminase enzyme 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. 10. The method of claim 4, wherein the Adenosine Deaminase enzyme, is conjugated with either of: ##STR00002## wherein n is a positive integer between 1 and about 5,000. 11. The method of claim 4, wherein the Adenosine Deaminase enzyme is a conjugate of formula: [R--NH].sub.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. 12. The method of claim 11, wherein the polyalkylene oxide is functionalized as: --C(.dbd.Y.sub.74)--(CH.sub.2).sub.m--(CH.sub.2CH.sub.2O).sub.n--, --C(.dbd.Y.sub.74)--Y--(CH.sub.2).sub.m--(CH.sub.2CH.sub.2O).sub.n--, --C(.dbd.Y.sub.74)--NR.sub.11--(CH.sub.2).sub.m--(CH.sub.2CH.sub.2O).sub.- n--, --CR.sub.75R.sub.76--(CH.sub.2).sub.m--(CH.sub.2CH.sub.2O).sub.n-- where R.sub.11, R.sub.75 and R.sub.76 are independently selected from among H, C.sub.1-6 alkyls, aryls, substituted aryls, aralkyls, heteroalkyls, substituted heteroalkyls and substituted C.sub.1-6 alkyls; m is zero or is a positive integer; Y.sub.74 is O or S; and n represents the degree of polymerization. 13. The method of claim 1, wherein the ADA enzyme or composition is formulated as a formulation or a pharmaceutical composition. 14. The method of claim 13, wherein the formulation or pharmaceutical composition 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. 15. The method of claim 1, wherein the administration to the individual in need thereof is: enteral or parenteral administration; or, oral, rectal, intravaginal, topical, subcutaneous, intradermal, intramuscular (IM), intravenous (IV) or intrathecal (IT) intracerebral, epidural, intracranial or rectal, nasal, or by inhalation or spray. 16. The method of claim 13, wherein the formulation or pharmaceutical composition 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. 17. The method of claim 13, wherein the effective amount of Adenosine Deaminase enzyme is: (a) from about 0.01 to about 100 mg/kg, or from about 5 to about 50 mg/kg, or from about 10 to about 30 mg/kg, subdivided into multiple administrations from a minimum of once a day to once a year; (b) from about 5 U/kg to about 50 U/kg, or from about 10 U/kg to about 30 U/kg, or from about 20 U/kg to about 60 U/kg, or from about 0.5 U/kg to about 5 U/kg; or a supraphysiological dose, in particular up to about 100 U/kg or more; (c) about 250 units/m I administered weekly, optionally administered subcutaneously or IM; or (d) any of (a) to (c), wherein the dosage is individualized based on monitoring of plasma Adenosine Deaminase enzyme, adenosine and/or other specific biomarkers after initial administrations. 18. The method of claim 13, wherein the effective amount of Adenosine Deaminase enzyme is administered in alternative dosing schedules, wherein optionally the dosing schedules comprise: a dosing schedule of about 10 U/kg, or between about 5 to 15 U/kg, Adagen, or about 0.067 mg/kg, or between about 0.001 to 0.12 mg/kg, EZN2279, for the first dose; about 15 U/kg, or between about 5 to 15 U/kg, Adagen, or about 0.1 mg/kg or between about 0.05 to 0.5 mg/kg, EZN2279, for the second dose, and/or about 30 U/kg Adagen, or between about 15 to 30 U/kg, or about 0.134 mg/kg, or between about 0.05 to 0.30 mg/kg, EZN2279 for the third dose, or a supraphysiological dose, in particular up to about 100 U/kg or more. 19. The method of claim 13, wherein an effective amount of the Adenosine Deaminase enzyme is administered any one of daily, twice a day, weekly, biweekly, monthly, or yearly. 20. The method of claim 1, wherein the ADA enzyme or composition is administered in combination with one or more of: (a) topical nitrates or calcium channel blockers for Raynaud's syndrome, antihistamines for pruritus, H2 blockers or proton pump inhibitors for esophageal symptoms, anti-diarrheal agents or anti-spasmotics for lower GI symptoms and ADEI/ARB medications for hypertension or other renal manifestations of systemic sclerosis; (b) immunosuppressive agents combining such agents as methotrexate, cyclophosphamide, mycophenolate mofetil, or rituximab; or (c) antibiotics, fluids, cytokines, immunoregulatory agents, anti-inflammatory agents, complement activating agents, carbohydrate-binding domains.

Details for Patent 10,391,154

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Leadiant Biosciences, Inc	ADAGEN	pegademase bovine	Injection	019818	03/21/1990		2037-07-19
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2037-07-19
Genentech, Inc.	RITUXAN HYCELA	rituximab and hyaluronidase human	Injection	761064	06/22/2017		2037-07-19