Anti-notch1 antibodies

Abstract

The present invention provides for antibodies that bind to Notch1. The present disclosure also provides methods of making the antibodies, pharmaceutical compositions comprising these antibodies and methods of treating disorders with the antibodies and pharmaceutical compositions.

What is claimed is: 
     
         1 . An antibody that binds to Notch1, comprising:
 a heavy chain variable region having a CDR1 region, a CDR2 region, and a CDR3 region from the heavy chain variable region comprising SEQ ID NO: 71.   
     
     
         2 . An antibody that binds to Notch1 comprising:
 a light chain variable region having a CDR1 region, a CDR2 region, and a CDR3 region from the light chain variable region comprising SEQ ID NO: 97.   
     
     
         3 . An antibody that binds to Notch1 comprising:
 a heavy chain variable region having a CDR1 region, a CDR2 region, and a CDR3 region from the heavy chain variable region as shown in SEQ ID NO: 71, and   a light chain variable region having a CDR1 region, a CDR2 region, and a CDR3 region from the light chain variable region as shown in SEQ ID NO: 97.   
     
     
         4 . The antibody according to any one of  claims 1 - 3 , comprising a heavy chain variable region amino acid sequence that is at least 90% identical to SEQ ID NO: 71. 
     
     
         5 . The antibody according to  claim 4 , comprising a heavy chain variable region amino acid sequence as set forth in SEQ ID NO: 71. 
     
     
         6 . The antibody according to any one of  claims 1 - 3 , comprising a light chain variable region amino acid sequence that is at least 90% identical to SEQ ID NO: 97. 
     
     
         7 . The antibody according to  claim 6 , comprising a light chain variable region amino acid sequence as set forth in SEQ ID NO: 97. 
     
     
         8 . The antibody according to any one of  claims 1 - 3 , comprising a heavy chain amino acid sequence that is at least 90% identical to SEQ ID NO: 111. 
     
     
         9 . The antibody according to  claim 8 , comprising a heavy chain amino acid sequence as set forth in SEQ ID NO: 111. 
     
     
         10 . The antibody according to any one of  claims 1 - 3 , comprising a light chain amino acid sequence that is at least 90% identical to SEQ ID NO: 113. 
     
     
         11 . The antibody according to  claim 10 , comprising a light chain amino acid sequence as set forth in SEQ ID NO: 113. 
     
     
         12 . An antibody that binds to Notch1, comprising:
 a heavy chain variable region amino acid sequence that is at least 90% identical to SEQ ID NO: 71; and   a light chain variable amino acid sequence that is at least 90% identical to SEQ ID NO: 97.   
     
     
         13 . An antibody that binds to Notch1, comprising:
 a heavy chain variable region amino acid sequence as set forth in SEQ ID NO: 71; and   a light chain variable amino acid sequence as set forth in SEQ ID NO: 97.   
     
     
         14 . An antibody that binds to Notch1, comprising:
 a heavy chain amino acid sequence that is at least 90% identical to SEQ ID NO: 111; and   a light chain amino acid sequence that is at least 90% identical to SEQ ID NO: 113.   
     
     
         15 . An antibody that binds to Notch1, comprising:
 a heavy chain amino acid sequence as set forth in SEQ ID NO: 111; and   a light chain amino acid sequence as set forth in SEQ ID NO: 113.   
     
     
         16 . An antibody that binds to Notch1 and competes for binding to Notch1 with the antibody of  claim 1 ,  2  or  3 . 
     
     
         17 . An antibody or antigen binding portion thereof, that binds to Notch1, wherein the antibody binds an epitope comprising at least 7 amino acid residues selected from Asn 1461, Lys 1462, Val 1463, Cys 1464, Leu 1466, Leu 1580, Tyr 1621, Gly 1622, Met 1670, Asp 1671, Val 1672, Arg 1673, Leu 1707, Ala 1708, Leu 1710, Leu 1711, Leu 1712, Leu 1713, Leu 1716 and Leu 1718. 
     
     
         18 . The antibody according to any one of  claims 1 - 17 , wherein said antibody is an IgA, IgD, IgE, IgG, or IgM molecule, or is derived therefrom. 
     
     
         19 . The antibody according to  claim 18 , wherein the antibody is an IgG, having a subclass selected from the group consisting of IgG1, IgG2, IgG3 and IgG4, or is derived therefrom. 
     
     
         20 . The antibody according to  claim 19 , wherein the subclass is derived from IgG1. 
     
     
         21 . A nucleic acid that encodes the antibody according to any one of  claims 1 - 20 . 
     
     
         22 . A nucleic acid comprising the sequence as set forth in SEQ ID NO: 112. 
     
     
         23 . A nucleic acid comprising the sequence as set forth in SEQ ID NO: 114. 
     
     
         24 . A vector comprising the nucleic acid according to any one of  claims 21 - 23 . 
     
     
         25 . A host cell comprising the vector of  claim 24 . 
     
     
         26 . A process for producing an antibody, comprising cultivating the host cell of  claim 25  and recovering the antibody from the culture media. 
     
     
         27 . A host cell that recombinantly produces the antibody according to any one of  claims 1 - 20 . 
     
     
         28 . A pharmaceutical composition comprising the antibody according to any one of  claims 1 - 20  and a pharmaceutically acceptable carrier. 
     
     
         29 . A method of treating a disorder in a subject in need thereof, comprising administering to said subject the antibody according to any one of  claims 1 - 20 , or the pharmaceutical composition of  claim 28 . 
     
     
         30 . The method of  claim 29 , wherein said disorder is associated with abnormal activation of Notch1. 
     
     
         31 . The method of  claim 29  or  30 , wherein said disorder is selected from the group consisting of T-cell acute lymphoblastic leukemia (T-ALL), non-small cell lung cancer (NSCLC) and breast cancer in a subject in need thereof. 
     
     
         32 . The antibody of any one of  claims 1 - 20  for use in therapy. 
     
     
         33 . The use of an antibody of any one of  claims 1 - 20  for the manufacture of a medicament. 
     
     
         34 . The use according to  claim 32  or  33 , wherein said use is for the treatment of T-cell acute lymphoblastic leukemia (T-ALL), non-small cell lung cancer (NSCLC) and breast cancer in a subject in need thereof. 
     
     
         35 . An antibody that binds to Notch1, comprising:
 a heavy chain variable region amino acid sequence as set forth in SEQ ID NO: 115; and   a light chain variable amino acid sequence as set forth in SEQ ID NO: 129.   
     
     
         36 . An antibody that binds to Notch1, comprising:
 a heavy chain amino acid sequence as set forth in SEQ ID NO: 149; and   a light chain amino acid sequence as set forth in SEQ ID NO: 151.   
     
     
         37 . An antibody that binds to human Notch1, wherein the antibody binds an epitope comprising at least 8 amino acid residues selected from Asp 1458, Asn 1461, Val 1463, Cys 1464, Leu 1466, Leu 1580, Met 1581, Pro 1582, Tyr 1621, Gly 1622, Arg 1623, Asp 1671, Val 1672, Arg 1673, Gly 1674, Leu 1710, Gly 1711, Ser 1712, Leu 1713, Asn 1714, Ile 1715, Pro 1716 and Lys 1718. 
     
     
         38 . An antibody that demonstrates higher inhibition of Notch1 activation of a mutant Notch1 receptor compared to inhibition of Notch1 activation of a native Notch1 receptor. 
     
     
         39 . A pharmaceutical composition comprising the antibody according to any one of  claims 35 - 38  and a pharmaceutically acceptable carrier. 
     
     
         40 . A method of treating a disorder in a subject in need thereof, comprising administering to said subject the antibody according to any one of  claims 35 - 38 , or the pharmaceutical composition of  claim 39 . 
     
     
         41 . The method of  claim 40 , wherein said disorder is associated with abnormal activation of Notch1. 
     
     
         42 . The method of  claim 40  or  41 , wherein said disorder is selected from the group consisting of T-cell acute lymphoblastic leukemia (T-ALL), non-small cell lung cancer (NSCLC) and breast cancer in a subject in need thereof. 
     
     
         43 . The antibody of any one of  claims 35 - 38  for use in therapy. 
     
     
         44 . The use of an antibody of any one of  claims 35 - 38  for the manufacture of a medicament. 
     
     
         45 . The use according to  claim 43  or  44 , wherein said use is for the treatment of T-cell acute lymphoblastic leukemia (T-ALL), non-small cell lung cancer (NSCLC) and breast cancer in a subject in need thereof.