Anti-plasma kallikrein antibodies

Abstract

Disclosed herein are antibodies capable of binding to plasma kallikrein and inhibit its activity. Such antibodies interact with one or more critical residues in the catalytic domain of the plasma kallikrein. The antibodies may also contain specific heavy chain complementarity determining region 3 (CDRs) motifs and optionally specific residues at certain positions within both the heavy chain variable region and the light chain variable region.

1 . An isolated antibody that binds human plasma kallikrein (PKal), wherein the antibody interacts with one or more of amino acid residues in the human PKal and inhibits its activity by at least 50%, wherein the amino acid residues are selected from the group consisting of V410, L412, T413, A414, Q415, R416, L418, C419, H434, C435, F436, D437, G438, L439, W445, Y475, K476, V477, S478, E479, G480, D483, F524, E527, K528, Y552, D554, Y555, A564, D572, A573, C574, K575, G576, S578, T596, S597, W598, G599, E600, G601, C602, A603, R604, Q607, P608, G609, V610, and Y611. 
     
     
         2 . The isolated antibody of  claim 1 , wherein the antibody binds an epitope of the PKal, the epitope comprising the segment selected from the group consisting of:
 (i) V410-C419,   (ii) H434-L439,   (iii) Y475-G480,   (iv) F524-K528,   (v) Y552-Y555,   (vi) D572-S578,   (vii) T596-R604, and   (viii) Q607-Y611.   
     
     
         3 . The isolated antibody of  claim 1 , wherein the antibody inhibits the activity of PKal by at least 80%. 
     
     
         4 . The isolated antibody of  claim 1 , wherein the antibody has an apparent Ki ( Ki,app ) lower than about 1 nM. 
     
     
         5 . The isolated antibody of  claim 4 , wherein the antibody has a K i,app  lower than about 0.1 nM. 
     
     
         6 . The isolated antibody of  claim 4 , wherein the antibody has a K i,app  lower than about 0.05 nM. 
     
     
         7 . The isolated antibody of  claim 1 , wherein the antibody has a binding affinity (K D ) for the PKal of less than 10 −6  M. 
     
     
         8 . The isolated antibody of  claim 1 , wherein the antibody preferentially binds the PKal as relative to a mutant of the PKal that contains one or more mutations at positions R551, Q553, Y555, T558, and R560. 
     
     
         9 . An isolated antibody that binds human plasma killikrein, wherein the antibody comprises a heavy chain variable region that comprises complementarity determining region 1 (HC CDR1), complementarity determining region 2 (HC CDR2), and complementarity determining region 3 (HC CDR3), and wherein the HC CDR3 comprises the motif X 99 R 100 X 101 G 102 X 103 P 104 R 105 X 106 X 107 X 108 X 109 X 110 X 111 , in which:
 X 99  is R or Q,   X 101  is T, I, R, S, or P,   X 103  is V, I, or L,   X 106  is R or W,   X 107  is D or N,   X 108  is A, S, D, E, or V,   X 109  is F or L,   X 110  is D, E, or N, and   X 111  is I, N, M, or S.   
     
     
         10 . The isolated antibody of  claim 9 , wherein the antibody inhibits the activity of PKal by at least 80%. 
     
     
         11 . The isolated antibody of  claim 9 , wherein the antibody has a K i,app  lower than about 1 nM. 
     
     
         12 . The isolated antibody of  claim 11 , wherein the antibody has a K i,app  lower than about 0.1 nM. 
     
     
         13 . The isolated antibody of  claim 12 , wherein the antibody has a K i,app  lower than about 0.05 nM. 
     
     
         14 . The isolated antibody of  claim 9 , wherein the antibody has a binding affinity (K D ) for the PKal of less than 10 −6  M. 
     
     
         15 . The isolated antibody of  claim 9 , wherein X 99  is Q and X 101  is I, R, S, or P. 
     
     
         16 . The isolated antibody of  claim 9 , wherein X 106  is W and X 111  is N, M, or S. 
     
     
         17 . The isolated antibody of  claim 9 , wherein X 101  is I, X 108  is E, and X 103  is I or L. 
     
     
         18 . The isolated antibody of  claim 9 , wherein X 101  is I and X 103  is I or L. 
     
     
         19 . The isolated antibody of  claim 9 , wherein X 103  is I or L and X 110  is D, E, or N. 
     
     
         20 . The isolated antibody of  claim 9 , wherein the heavy chain variable region includes H 31  in the HC CDR1. 
     
     
         21 . The isolated antibody of  claim 9 , wherein the heavy chain variable region includes F 27 , F 29 , or both in the framework region 1 (FR1). 
     
     
         22 . The isolated antibody of  claim 9 , further comprising a light chain variable region that comprises complementarity determining region 1 (LC CDR1), complementarity determining region 2 (LC CDR2), and complementarity determining region 3 (LC CDR3). 
     
     
         23 . The isolated antibody of  claim 22 , wherein the LC CDR2 includes K 50 , L 54 , E 55 , S 56 , or a combination thereof. 
     
     
         24 . The isolated antibody of  claim 23 , wherein the light chain variable region further includes G 57  in the framework region 3 (FR3). 
     
     
         25 . The isolated antibody of  claim 22 , wherein the light chain variable includes N 45  in the framework region 2 (FR2). 
     
     
         26 . The isolated antibody of  claim 1 , wherein the antibody is a full-length antibody or an antigen-binding fragment thereof. 
     
     
         27 . The isolated antibody of  claim 1 , wherein the antibody is a human antibody or a humanized antibody. 
     
     
         28 . The isolated antibody of  claim 1 , wherein the antibody preferentially bind an active PKal. 
     
     
         29 . A pharmaceutical composition comprising an antibody of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         30 . A method for treating a disease associated with plasma kallikrein, comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of  claim 29 . 
     
     
         31 . The method of  claim 30 , wherein the subject is a human patient diagnosed with, suspected of having, or at risk for the disease.