Highly concentrated low viscosity masp-2 inhibitory antibody formulations, kits, and methods

Abstract

The present invention relates to stable, high-concentration low-viscosity formulations of MASP-2 inhibitory antibodies, kits comprising the formulations and therapeutic methods using the formulations and kits for inhibiting the adverse effects of MASP-2 dependent complement activation.

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows: 
     
         1 . A method of treating a subject suffering from a MASP-2-dependent complement-associated disease or disorder comprising administering a liquid formulation the subject in need thereof, wherein the liquid formulation comprises:
 (a) a buffer system having a pH of 5.0 to 7.0, wherein the buffer system comprises at least one pharmaceutically acceptable buffering agent-selected from the group consisting of citrate at a concentration of 10 mM to 50 mM and histidine at a concentration of 10 mM to 50 mM; and   (b) a-human IgG4 monoclonal antibody that specifically binds to human MASP-2 at a concentration of about 50 mg/mL to about 250 mg/mL, wherein said antibody comprises (i) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:2 and (ii) a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:3; and   (c) L-arginine or L-arginine HCl at a concentration from 200 mM to 300 mM in the amount sufficient for the formulation to be hypertonic; and   (d) a nonionic surfactant selected from a polysorbate or a poloxamer at a concentration of from 0.01% (w/v) to 0.1% (w/v).   
     
     
         2 . The method of  claim 1 , wherein the concentration of the antibody in the liquid formulation is from about 100 mg/mL to about 225 mg/mL, or from about 150 mg/mL to about 200 mg/mL, or from about 175 mg/mL to about 195 mg/mL. 
     
     
         3 . The method of  claim 1 , wherein the liquid formulation has a viscosity of between 2 and 50 centipoise (cP) when measured at 25° C. with a shear rate in the range of 100,000 to 250,000 1/sec. 
     
     
         4 . The method of  claim 1 , wherein the at least one buffering agent is citrate present in the liquid formulation at a concentration of 10 mM to 50 mM. 
     
     
         5 . The method of  claim 1 , wherein the surfactant is polysorbate 80. 
     
     
         6 . The method of  claim 1 , wherein the liquid formulation is stable when stored between 2° C. and 8° C. for at least 12 months. 
     
     
         7 . The method of  claim 1 , wherein the liquid formulation comprises 20 mM sodium citrate, 200 mM L-arginine HCl, and from 0.001% w/v to 0.05% w/v polysorbate 80, and wherein the concentration of the antibody in the formulation is from about 175 mg/mL to about 195 mg/mL. 
     
     
         8 . The method of  claim 1 , wherein the liquid formulation consists essentially of:
 (a) polysorbate 80 at a concentration from about 0.01 to about 0.08% w/v;   (b) L-arginine HCl at a concentration from about 150 mM to about 200 mM;   (c) sodium citrate at a concentration from about 10 mM to about 50 mM; and   (d) the monoclonal antibody that specifically binds to human MASP-2 at a concentration of about 150 mg/mL to about 200 mg/mL.   
     
     
         9 . The method of  claim 1 , wherein the concentration of the monoclonal antibody that specifically binds to human MASP-2 in the liquid formulation is from about 175 mg/mL to about 195 mg/mL. 
     
     
         10 . The method of  claim 1 , wherein the monoclonal antibody that specifically binds to human MASP-2 is a tetramer consisting of two identical heavy chains having the amino acid sequence set forth in SEQ ID NO:4 and two identical light chains having the amino acid sequence set forth in SEQ ID NO:5. 
     
     
         11 . The method of  claim 1 , wherein the MASP-2-dependent complement-associated disease or disorder is selected from the group consisting of a thrombotic microangiopathy (TMA), a renal condition, an inflammatory reaction resulting from tissue or organ transplantation, an ischemia reperfusion injury, a complication associated with diabetes, a cardiovascular disease or disorder, an inflammatory gastrointestinal disorder, a pulmonary disorder, an ophthalmic disease or disorder, and disseminated intravascular coagulation. 
     
     
         12 . The method of  claim 11 , wherein the thrombotic microangiopathy is atypical hemolytic syndrome (aHUS). 
     
     
         13 . The method of  claim 11 , wherein the thrombotic microangiopathy is associated with hematopoietic stem cell transplant. 
     
     
         14 . The method of  claim 11 , wherein the renal condition is IgA nephropathy. 
     
     
         15 . The method of  claim 11 , wherein the renal condition is lupus nephritis.