ANTI IgE ANTIBODIES

Abstract

The present invention relates to novel human antibodies specifically directed against human immunoglobulin E (anti-IgE). The present invention also relates to pharmaceutical compositions and methods for treating asthma, in particular allergic asthma, as well as other IgE-mediated disorders including allergic rhinitis and food allergies.

1 . A human monoclonal antibody or an antigen-binding portion thereof directed against human IgE, the antibody or portion having at least one additional property selected from the group consisting of:
 a) has an IC 50  of 0.5 μg/mL or less as measured by its ability to reduce IgE cell binding assay using an RBL-2H3 cell line transfected with the human FcεR1;   b) has an IC 50  of 0.5 μg/mL or less as measured by its ability to inhibit IgE-mediated degranulation of an RBL-2H3 cell line transfected with the human FcεR1;   c) does not crosslink receptor-bound IgE and does not stimulate IgE-dependent degranulation of RBL-2H3 (FcεR1) cells cultured with human IgE;   d) does not crosslink receptor-bound IgE and does not stimulate IgE-dependent degranulation of human blood basophils;   e) is highly selective for IgE over human IgA, IgG1 and IgG3;   f) binds to the full length of human IgE with an Affinity Constant, K D , of 15 nM or less as measured by surface plasmon resonance;   g) has an off rate (kOff) for human IgE of 2×10 −4  s −1  or smaller as measured by surface plasmon resonance; and   h) binds to the same epitope of human IgE as an antibody selected from the group consisting of recombinant 5.396.1; 5.396.1 Hc-S103N Lc-K61R; recombinant 6.605.1; 6.605.1 (H3Q,M13K,D82E-T25A,T53S); recombinant 5.948.1; and 5.948.1 H100Y.   
     
     
         2 . An isolated human antibody or an antigen-binding portion thereof directed against human IgE, wherein said antibody has an IC 25ng/mL (100-5000 ng/mL) of about 0.1-30 μg/mL, wherein the IC 25ng/mL (100-5000 ng/mL) is defined as the in vitro concentration of antibody required to reduce the free IgE concentration in a serum sample from an initial concentration in the range of about 100-5000 ng/mL to a concentration of about 25 ng/mL. 
     
     
         3 . The antibody or portion according to  claim 2 , wherein said antibody has an IC 25ng/mL (500-1500 ng/mL) of about 1-30 μg/mL, wherein the IC 25ng/mL (500-1500 ng/mL) is defined as the in vitro concentration of antibody required to reduce the free IgE concentration in a serum sample from an initial concentration in the range of about 500-1500 ng/mL to a concentration of about 25 ng/mL. 
     
     
         4 . The antibody or portion according to  claim 1  or  2 , wherein said antibody comprises an H-CDR3 having a sequence selected from the group consisting of SEQ ID NOs: 10, 30, 50, 70, 90 and 130. 
     
     
         5 . The antibody or portion according to  claim 1  or  2 , wherein said antibody is selected from the group consisting of:
 an antibody comprising a set of H-CDRs (H-CDR1, H-CDR2, and H-CDR3) respectively having the sequences of SEQ ID NOs: 6, 8, and 10; and a set of L-CDRs (L-CDR1, L-CDR2, and L-CDR3) respectively having the sequences of SEQ ID NOs: 16, 18, and 20; 
 an antibody comprising a set of H-CDRs (H-CDR1, H-CDR2, and H-CDR3) respectively having the sequences of SEQ ID NOs: 26, 28, and 30; and a set of L-CDRs (L-CDR1, L-CDR2, and L-CDR3) respectively having the sequences of SEQ ID NOs: 36, 38, and 40; 
 an antibody comprising a set of H-CDRs (H-CDR1, H-CDR2, and H-CDR3) respectively having the sequences of SEQ ID NOs: 46, 48, and 50; and a set of L-CDRs (L-CDR1, L-CDR2, and L-CDR3) respectively having the sequences of SEQ ID NOs: 56, 58, and 60; 
 an antibody comprising a set of H-CDRs (H-CDR1, H-CDR2, and H-CDR3) respectively having the sequences of SEQ ID NOs: 66, 68, and 70; and a set of L-CDRs (L-CDR1, L-CDR2, and L-CDR3) respectively having the sequences of SEQ ID NOs: 76, 78, and 80; 
 an antibody comprising a set of H-CDRs (H-CDR1, H-CDR2, and H-CDR3) respectively having the sequences of SEQ ID NOs: 86, 88, and 90; and a set of L-CDRs (L-CDR1, L-CDR2, and L-CDR3) respectively having the sequences of SEQ ID NOs: 96, 98, and 100; and 
 an antibody comprising a set of H-CDRs (H-CDR1, H-CDR2, and H-CDR3) respectively having the sequences of SEQ ID NOs: 126, 128, and 130; and a set of L-CDRs (L-CDR1, L-CDR2, and L-CDR3) respectively having the sequences of SEQ ID NOs: 136, 138, and 140. 
 
     
     
         6 . The antibody or portion according to  claim 1  or  2 , wherein said antibody is of the IgG1 or IgG2 subtype. 
     
     
         7 . The antibody or portion according to  claim 1  or  2 , wherein said antibody is selected from the group consisting of:
 an antibody comprising an H-variable domain having the sequence of SEQ ID NO: 4; and an L-variable domain having the sequence of SEQ ID NO: 14; 
 an antibody comprising an H-variable domain having the sequence of SEQ ID NO: 24; and an L-variable domain having the sequence of SEQ ID NO: 34; 
 an antibody comprising an H-variable domain having the sequence of SEQ ID NO: 44; and an L-variable domain having the sequence of SEQ ID NO: 54; 
 an antibody comprising an H-variable domain having the sequence of SEQ ID NO: 64; and an L-variable domain having the sequence of SEQ ID NO: 74; 
 an antibody comprising an H-variable domain having the sequence of SEQ ID NO: 84; and an L-variable domain having the sequence of SEQ ID NO: 94; and 
 an antibody comprising an H-variable domain having the sequence of SEQ ID NO: 124; and an L-variable domain having the sequence of SEQ ID NO: 134. 
 
     
     
         8 . The antibody or portion according to  claim 1  or  2 , wherein said antibody is selected from the group consisting of:
 an antibody comprising an H-chain having the sequence of SEQ ID NO: 2; and an L-chain having the sequence of SEQ ID NO: 12; 
 an antibody comprising an H-chain having the sequence of SEQ ID NO: 22; and an L-chain having the sequence of SEQ ID NO: 32; 
 an antibody comprising an H-chain having the sequence of SEQ ID NO: 42; and an L-chain having the sequence of SEQ ID NO: 52; 
 an antibody comprising an H-chain having the sequence of SEQ ID NO:62; and an L-chain having the sequence of SEQ ID NO: 72; 
 an antibody comprising an H-chain having the sequence of SEQ ID NO: 82; and an L-chain having the sequence of SEQ ID NO: 92; and 
 an antibody comprising an H-chain having the sequence of SEQ ID NO: 122; and an L-chain having the sequence of SEQ ID NO: 132. 
 
     
     
         9 . The antibody or portion according to  claim 1  or  2 , wherein said antibody is selected from the group consisting of:
 an antibody comprising an H-chain sequence encoded by a nucleic acid sequence of SEQ ID NO: 1; and an L-chain sequence encoded by a nucleic acid sequence of SEQ ID NO: 11; 
 an antibody comprising an H-chain sequence encoded by a nucleic acid sequence of SEQ ID NO: 21; and an L-chain sequence encoded by a nucleic acid sequence of SEQ ID NO: 31; 
 an antibody comprising an H-chain sequence encoded by a nucleic acid sequence of SEQ ID NO: 41; and an L-chain sequence encoded by a nucleic acid sequence of SEQ ID NO: 51; 
 an antibody comprising an H-chain sequence encoded by a nucleic acid sequence of SEQ ID NO: 61; and an L-chain sequence encoded by a nucleic acid sequence of SEQ ID NO: 71; 
 an antibody comprising an H-chain sequence encoded by a nucleic acid sequence of SEQ ID NO: 81; and an L-chain sequence encoded by a nucleic acid sequence of SEQ ID NO: 91; and 
 an antibody comprising an H-chain sequence encoded by a nucleic acid sequence of SEQ ID NO: 121; and an L-chain sequence encoded by a nucleic acid sequence of SEQ ID NO: 131. 
 
     
     
         10 . A variant of an antibody or portion according to  claim 1  or  2 , wherein said variant differs from the antibody or portion by 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions. 
     
     
         11 . A nucleic acid sequence encoding one of the chains of an antibody or portion according to  claim 1  or  2 . 
     
     
         12 . A vector comprising a nucleic acid sequence according to  claim 11 . 
     
     
         13 . A vector suitable for expressing one of the chains of an antibody or portion according to  claim 1  or  2 . 
     
     
         14 . A cell expressing one of the chains of an antibody or portion according to  claim 1  or  2 . 
     
     
         15 . A method for making an antibody or portion according to  claim 1  or  2 , comprising culturing a cell according to  claim 14 , and retrieving said antibody or portion. 
     
     
         16 . (canceled) 
     
     
         17 . (canceled) 
     
     
         18 . A pharmaceutical composition comprising an antibody or portion according to  claim 1  or  2 . 
     
     
         19 . The pharmaceutical composition according to  claim 18 , for the treatment of an IgE-mediated disorder selected from the group consisting of asthma, allergic asthma, allergic rhinitis and food allergies. 
     
     
         20 . A method for treating an IgE-mediated disorder selected from the group consisting of asthma, allergic asthma, allergic rhinitis and food allergies in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of an antibody or portion according to  claim 1  or  2 . 
     
     
         21 . (canceled) 
     
     
         22 . A nucleic acid sequence selected from the group consisting of SEQ ID NOs: 1, 3, 11, 13, 21, 23, 31, 33, 41, 43, 51, 53, 61, 63, 71, 73, 81, 83, 91, 93, 101, 103, 105, 107, 109, 111, 121, 123, 131 and 133. 
     
     
         23 . An antibody or an antigen-binding portion thereof directed against human IgE, wherein said antibody is selected from the group consisting of:
 an antibody comprising an H-variable domain having the sequence of SEQ ID NO: 4; and an L-variable domain having the sequence of SEQ ID NO: 14;   an antibody comprising an H-variable domain having the sequence of SEQ ID NO: 24; and an L-variable domain having the sequence of SEQ ID NO: 34;   an antibody comprising an H-variable domain having the sequence of SEQ ID NO: 44; and an L-variable domain having the sequence of SEQ ID NO: 54;   an antibody comprising an H-variable domain having the sequence of SEQ ID NO: 64; and an L-variable domain having the sequence of SEQ ID NO: 74;   an antibody comprising an H-variable domain having the sequence of SEQ ID NO: 84; and an L-variable domain having the sequence of SEQ ID NO: 94;   an antibody comprising an H-variable domain having the sequence of SEQ ID NO: 124; and an L-variable domain having the sequence of SEQ ID NO: 134;   an antibody comprising an H-chain having the sequence of SEQ ID NO: 2; and an L-chain having the sequence of SEQ ID NO: 12;   an antibody comprising an H-chain having the sequence of SEQ ID NO: 22; and an L-chain having the sequence of SEQ ID NO: 32;   an antibody comprising an H-chain having the sequence of SEQ ID NO: 42; and an L-chain having the sequence of SEQ ID NO: 52;   an antibody comprising an H-chain having the sequence of SEQ ID NO: 62; and an L-chain having the sequence of SEQ ID NO: 72;   an antibody comprising an H-chain having the sequence of SEQ ID NO: 82; and an L-chain having the sequence of SEQ ID NO: 92;   an antibody comprising an H-chain having the sequence of SEQ ID NO: 122; and an L-chain having the sequence of SEQ ID NO: 132;   an antibody comprising an H-chain encoded by the plasmid insert of ATCC deposit PTA-7977; and an L-chain encoded by the plasmid insert of ATCC deposit PTA-7982;   an antibody comprising an H-chain encoded by the plasmid insert of ATCC deposit PTA-7981; and an L-chain encoded by the plasmid insert of ATCC deposit PTA-7980;   an antibody comprising an H-chain encoded by the plasmid insert of ATCC deposit PTA-7985; and an L-chain encoded by the plasmid insert of ATCC deposit PTA-7984;   an antibody comprising an H-chain encoded by the plasmid insert of ATCC deposit PTA-7983; and an L-chain encoded by the plasmid insert of ATCC deposit PTA-7978; and   an antibody comprising an H-chain encoded by the plasmid insert of ATCC deposit PTA-7979; and an L-chain encoded by the plasmid insert of ATCC deposit PTA-7986.   
     
     
         24 - 36 . (canceled) 
     
     
         37 . A pharmaceutical composition comprising an antibody or portion according to  claim 23 . 
     
     
         38 . The pharmaceutical composition according to  claim 37 , for the treatment of an IgE-mediated disorder selected from the group consisting of asthma, allergic asthma, allergic rhinitis and food allergies. 
     
     
         39 . A method for treating an IgE-mediated disorder selected from the group consisting of asthma, allergic asthma, allergic rhinitis and food allergies in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of an antibody or portion according to  claim 23 . 
     
     
         40 . (canceled) 
     
     
         41 . A nucleic acid sequence encoding one of the chains of an antibody or portion according to  claim 23 . 
     
     
         42 . A vector comprising a nucleic acid sequence according to  claim 41 . 
     
     
         43 . A vector suitable for expressing one of the chains of an antibody or portion according to  claim 23 . 
     
     
         44 . A cell expressing one of the chains of an antibody or portion according to  claim 23 . 
     
     
         45 . A method for making an antibody or portion according to  claim 23 , comprising culturing a cell according to  claim 43 , and retrieving said antibody or portion. 
     
     
         46 . A method for reducing IgE binding FcεR1, comprising contacting the IgE with an anti-IgE antibody or antigen-binding portion according to  claim 1 ,  2 , or  23 . 
     
     
         47 . A method for reducing IgE-mediated degranulation by a cell, comprising contacting the cell with an anti-IgE antibody or antigen-binding portion according to  claim 1 ,  2 , or  23 .