Plasma kallikrein inhibitors and uses thereof for treating hereditary angioedema attack

Abstract

Provided herein are plasma kallikrein antibodies binding to active plasma kallikrein and methods of using such antibodies in treating and preventing hereditary angioedema attack, such method may involve a first treatment period and optionally, a second treatment period. Also provided are methods of using such antibodies in treating hereditary angioedema involving a single dose of the antibody to a subject who has undergone a prior HAE treatment, followed by multiple doses of the same antibody if the subject experiences an HAE attack after the single dose.

1 . A method for treating hereditary angioedema (HAE) attack or reducing the rate of HAE attack, the method comprising:
 (i) administering to a subject in need thereof an antibody at multiple doses of about 150 mg or about 300 mg in a first treatment period, wherein the antibody comprises a heavy chain complementarity determining region (HCDR) 1 set forth as HYIMM (SEQ ID NO: 5), a HCDR2 set forth as GIYSSGGITVYADSVKG (SEQ ID NO: 6), a HCDR3 set forth as RRIGVPRRDEFDI (SEQ ID NO: 7) and light chain complementarity determining region (LCDR) 1 set forth as RASQSISSWLA (SEQ ID NO: 8), a LCDR2 set forth as KASTLES (SEQ ID NO: 9), and a LCDR3 set forth as QQYNTYWT (SEQ ID NO: 10);   and   (ii) further administering the antibody to the subject for a second treatment period after (i);   wherein the subject is a human patient who had experienced at least two HAE attacks per year prior to the first treatment period.   
     
     
         2 . The method of  claim 1 , wherein the antibody comprises a heavy chain variable domain set forth as EVQLLESGGGLVQPGGSLRLSCAASGFTFSHYIMMWVRQAPGKGLEWVSGIYSSGGITV YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAYRRIGVPRRDEFDIWGQGTM VTVSS (SEQ ID NO: 3) and a light chain variable domain set forth as DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYKASTLESGVPS RFSGSGSGTEFTLTISSLQPDDFATYYCQQYNTYWTFGOGTKVEIK (SEQ ID NO: 4). 
     
     
         3 . The method of  claim 1 , wherein the antibody is a full length antibody or an antigen-binding fragment thereof. 
     
     
         4 . The method of  claim 3 , wherein the antibody is an IgG molecule. 
     
     
         5 . The method of  claim 4 , wherein the antibody is an IgG1 molecule. 
     
     
         6 . The method of  claim 1 , wherein the antibody is administered in multiple doses of about 300 mg every two weeks or every four weeks. 
     
     
         7 . The method of  claim 1 , wherein the antibody is formulated in a pharmaceutical composition comprising a pharmaceutically acceptable carrier. 
     
     
         8 . The method of  claim 7 , wherein the pharmaceutically composition comprises sodium phosphate, citric acid, histidine, sodium chloride, and polysorbate 80. 
     
     
         9 . The method of  claim 8 , wherein the sodium phosphate is at a concentration of about 30 mM, the citric acid is at a concentration of about 19 mM, the histidine is at a concentration of about 50 mM, the sodium chloride is at a concentration of about 90 mM, and the polysorbate 80 is at about 0.01%. 
     
     
         10 . The method of  claim 1 , wherein the antibody is administered subcutaneously. 
     
     
         11 . The method of  claim 1 , wherein the subject is a human patient having, suspected of having, or at risk for HAE, optionally, wherein the subject has HAE type I or type II. 
     
     
         12 . (canceled) 
     
     
         13 . (canceled) 
     
     
         14 . The method of  claim 1 , wherein the subject is a human patient who has received one or more prior HAE treatments prior to the first treatment period. 
     
     
         15 . The method of  claim 14 , wherein the prior HAE treatment comprises an C1-inhibitor, a plasma kallikrein inhibitor, a bradykinin receptor antagonist, an androgen, an anti-tranexamic acid, or a combination thereof. 
     
     
         16 . The method of  claim 15 , wherein the prior HAE treatment comprises an C1-INH, ecallantide, icatibant, danazol, tranexamic acid, or a combination thereof. 
     
     
         17 . The method of  claim 1 , wherein the method comprises a tapering period for the one or more prior HAE treatments. 
     
     
         18 . (canceled) 
     
     
         19 . The method of  claim 1 , wherein the one or more prior HAE treatments terminate either before the first dose of the antibody or within three weeks after the first dose of the antibody. 
     
     
         20 . The method of  claim 1 , wherein the subject is a human patient who is free of prior HAE treatment. 
     
     
         21 . (canceled) 
     
     
         22 . (canceled) 
     
     
         23 . The method of  claim 1 , wherein the first treatment period is 26 weeks or longer and/or the second treatment period is 26 weeks or longer. 
     
     
         24 .- 26 . (canceled) 
     
     
         27 . The method of  claim 23 , wherein the second treatment period comprises one or more doses of the antibody at about 300 mg, optionally wherein the second treatment period comprises multiple doses of the antibody at about 300 mg every two weeks. 
     
     
         28 . (canceled) 
     
     
         29 . The method of  claim 1 , wherein the subject is a human patient free of a long-term prophylaxis for HAE, or an HAE treatment involving an angiotensin-converting enzyme (ACE) inhibitor, an estrogen-containing medication, or an androgen prior to the first treatment period, during the first treatment period, and/or during the second treatment period. 
     
     
         30 .- 59 . (canceled)