US2014004121A1PendingUtilityA1

Anti-mesothelin binding proteins

61
Assignee: AMGEN INCPriority: Jun 27, 2012Filed: Jun 25, 2013Published: Jan 2, 2014
Est. expiryJun 27, 2032(~5.9 yrs left)· nominal 20-yr term from priority
Inventors:William C. Fanslow, IiiCarl KozloskyJean Gudas
C07K 2317/732C07K 16/30C07K 2317/622C07K 2317/72C07K 16/2809C07K 2317/21C07K 16/3046A61P 35/00C07K 16/28A61K 2039/505C07K 16/468C07K 2317/31C07K 2317/33G01N 33/6893C07K 2317/734C07K 2317/92
61
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Claims

Abstract

The present disclosure provides compositions and methods relating to antigen binding proteins, in particular, antibodies and bispecific antibodies which specifically bind to mesothelin. The disclosure provides nucleic acids encoding such antigen binding proteins and antibodies and methods of making and using such antibodies, including methods of treating and preventing cancer or other hypoproliferative disorders and related disorders by administering such antigen binding proteins and antibodies to a subject in need of such treatment.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . An isolated anti-mesothelin human antibody or antigen binding protein or fragment thereof, wherein said antibody has at least one of the following properties:
 a. binds to a different epitope than the MORAb-009 antibody;   b. competes for binding with Ab237;   c. specifically binds to human, cyno, rat and murine mesothelin;   d. does not internalize upon binding to mesothelin;   e. when bound to mesothelin, does not inhibit CA125 interaction with mesothelin;   f. has a binding affinity K D  of at least 5.0 pM against human mesothelin;   g. has enhanced effector function;   h. binds to membrane-bound mesothelin preferentially over soluble mesothelin;   i. reduces the growth of mesothelin expressing tumor cells in vivo.   
     
     
         2 . The antibody or antigen binding protein of  claim 1 , wherein said antibody or antigen binding protein exhibits at least two of the listed properties. 
     
     
         3 . The antibody or antigen binding protein of  claim 1 , wherein said antibody or antigen binding protein exhibits at least three of the listed properties. 
     
     
         4 . The antibody or antigen binding protein of  claim 1 , wherein said antibody or antigen binding protein exhibits at least four of the listed properties. 
     
     
         5 . The antibody or antigen binding protein of  claim 1 , wherein said antibody or antigen binding protein exhibits at least five of the listed properties. 
     
     
         6 . The antibody or antigen binding protein of  claim 1 , wherein said antibody or antigen binding protein exhibits at least six of the listed properties. 
     
     
         7 . The antibody or antigen binding protein of  claim 1 , wherein said antibody or antigen binding protein exhibits at least seven of the listed properties. 
     
     
         8 . The antibody or antigen binding protein of  claim 1 , wherein said antibody or antigen binding protein exhibits at least eight of the listed properties. 
     
     
         9 . The antibody or antigen binding protein of  claim 1 , wherein said antibody or antigen binding protein exhibits nine of the listed properties. 
     
     
         10 . An isolated antibody or antigen binding protein or fragment thereof, wherein the antibody or antigen binding protein or fragment thereof specifically binds to mesothelin and comprises 3 heavy chain CDRs and 3 light chain CDRs with sequences selected from the group consisting of:
 a. SEQ ID NOs: 45, 46, 47 of the heavy chain and SEQ ID NOs: 9, 10, 11 of the light chain;   b. SEQ ID NOs: 48, 49, 50 of the heavy chain and SEQ ID NOs: 12, 13, 14 of the light chain;   c. SEQ ID NOs: 51, 52, 53 of the heavy chain and SEQ ID NOs: 15, 16, 17 of the light chain;   d. SEQ ID NOs: 51, 52, 53 of the heavy chain and SEQ ID NOs: 18, 19, of the light chain;   e. SEQ ID NOs: 54, 55, 56 of the heavy chain and SEQ ID NOs: 21, 22, 23 of the light chain;   f. SEQ ID NOs: 57, 58, 59 of the heavy chain and SEQ ID NOs: 24, 25, 26 of the light chain;   g. SEQ ID NOs: 60, 61, 62 of the heavy chain and SEQ ID NOs: 27, 28, 29 of the light chain;   h. SEQ ID NOs: 63, 64, 65 of the heavy chain and SEQ ID NOs: 30, 31, 32 of the light chain;   i. SEQ ID NOs: 63, 64, 65 of the heavy chain and SEQ ID NOs: 33, 34, of the light chain; and   j. SEQ ID NOs: 63, 64, 65 of the heavy chain and SEQ ID NOs: 36, 37, 38 of the light chain   
       wherein each of said CDRs are identical to or comprise 1, 2, or 3 amino acid residue substitutions relative to their specified sequence. 
     
     
         11 . An isolated antibody or antigen binding protein or fragment thereof, wherein the antibody or antigen binding protein or fragment thereof specifically binds mesothelin and comprises a heavy chain variable domain and a light chain variable domain selected from the group consisting of:
 a. a heavy chain variable domain comprising SEQ ID NO: 86 and a light chain variable domain comprising SEQ ID NO: 72;   b. a heavy chain variable domain comprising SEQ ID NO: 87 and a light chain variable domain comprising SEQ ID NO: 73;   c. a heavy chain variable domain comprising SEQ ID NO: 88 and a light chain variable domain comprising SEQ ID NO: 74;   d. a heavy chain variable domain comprising SEQ ID NO: 88 and a light chain variable domain comprising SEQ ID NO: 75;   e. a heavy chain variable domain comprising SEQ ID NO: 89 and a light chain variable domain comprising SEQ ID NO: 76;   f. a heavy chain variable domain comprising SEQ ID NO: 90 and a light chain variable domain comprising SEQ ID NO: 77;   g. a heavy chain variable domain comprising SEQ ID NO: 91 and a light chain variable domain comprising SEQ ID NO: 78;   h. a heavy chain variable domain comprising SEQ ID NO: 92 and a light chain variable domain comprising SEQ ID NO: 79;   i. a heavy chain variable domain comprising SEQ ID NO: 92 and a light chain variable domain comprising SEQ ID NO: 80;   j. a heavy chain variable domain comprising SEQ ID NO: 92 and a light chain variable domain comprising SEQ ID NO: 81;   k. a heavy chain variable domain comprising SEQ ID NO: 93 and a light chain variable domain comprising SEQ ID NO: 82;   l. a heavy chain variable domain comprising SEQ ID NO: 94 and a light chain variable domain comprising SEQ ID NO: 83;   
       wherein each of said heavy chain variable domain and light chain variable domain have at least 90% identity relative to their specified sequence. 
     
     
         12 . The isolated antibody or antigen binding protein or fragment thereof of  claim 11 , wherein said heavy chain variable domain and light chain variable domain have at least 95% identity relative to their specified sequence. 
     
     
         13 . The isolated antibody or antigen binding protein or fragment thereof of  claim 11 , wherein said heavy chain variable domain and light chain variable domain are 100% identical to their specified sequence. 
     
     
         14 . The antibody of  claim 1 , wherein said antibody or antigen binding protein or fragment thereof is a bispecific antibody and binds an additional target other than MSLN. 
     
     
         15 . The antibody or antigen binding protein or fragment thereof of  claim 14 , wherein said additional target is CD3. 
     
     
         16 . The antibody or antigen binding protein or fragment thereof of  claim 15 , wherein said CD3 is human and/or cynomolgus CD3. 
     
     
         17 . The antibody or antigen binding protein or fragment thereof of  claim 15 , wherein said CD3 is human and/or mouse and/or rat and/or cynomolgus CD3. 
     
     
         18 . The antibody or antigen binding protein or fragment thereof of  claim 15 , wherein said antibody further comprises a variable heavy chain region (VH) as set forth in SEQ ID NO: 118 and a variable light chain region (VL) as set forth in SEQ ID NO: 120. 
     
     
         19 . The antibody or antigen binding protein or fragment thereof of  claim 15 , wherein said antibody further comprises
 a. a VH CDR1 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 115;   b. a VH CDR2 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 116;   c. a VH CDR3 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 117;   d. a VL CDR1 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 112;   e. a VL CDR2 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 113; and   f. a VL CDR3 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 114.   
     
     
         20 . The antibody or antigen binding protein or fragment thereof of  claim 15 , wherein said antibody further comprises a VH and VL set forth in SEQ ID NO: 122. 
     
     
         21 . A bispecific single chain antibody, said bispecific single chain antibody comprising binding domains specific for CD3 and MSLN, wherein the corresponding variable heavy chain regions (V H ) and the corresponding variable light chain regions (V L ) regions are arranged, from N-terminus to C-terminus, in the order, V H (MSLN)-V L (MSLN)-V H (CD3)-V L (CD3), or V H (CD3)-V L (CD3)-V H (MSLN)-V L (MSLN), or V L (MSLN)-V H (MSLN)-V H (CD3)-V L (CD3), or V H (CD3)-V L (CD3)-V L (MSLN)-V H (MSLN), or VL(MSLN)-V H (MSLN)-V L (CD3)-V H (CD3), or V L (CD3)-V H (CD3)-V L (MSLN)-V H (MSLN), or V H (MSLN)-V L (MSLN)-V L (CD3)-V H (CD3), or V L (CD3)-V H (CD3)-V H (MSLN)-V L (MSLN). 
     
     
         22 . The bispecific single chain antibody of  claim 21 , wherein said CD3 is human and/or cynomolgus and/or mouse and/or rat CD3 and said MSLN is human and/or cynomolgus and/or mouse and/or rat MSLN. 
     
     
         23 . The bispecific single chain antibody of  claim 21 , wherein said V H (MSLN) are set forth in SEQ ID NOs: 86-94, said V L (MSLN) are set forth in SEQ ID NOs: 72-83, said VH (CD3) are set forth in SEQ ID NO: 118, and said VL (CD3) are set forth in SEQ ID NO: 120. 
     
     
         24 . The bispecific single chain antibody of  claim 21 , wherein said VH (MSLN) comprises CDRs 1-3 having the sequences set forth in SEQ ID NOs: 45, 46, and 47, respectively, said VL (MSLN) comprises CDRs 1-3 having the sequences set forth in SEQ ID NOs: 9, 10, and 11, respectively, said VH (CD3) comprises CDRs 1-3 having the sequences set forth in SEQ ID NOs: 115, 116, and 117, respectively, and said VL(CD3) comprises CDRs 1-3 having the sequences set forth in SEQ ID NOs: 112, 113, and 114, respectively. 
     
     
         25 . A bispecific single chain antibody that comprises a first VH as set forth in SEQ ID NO: 86, a first VL as set forth in SEQ ID NO: 72, a second VH as set forth in SEQ ID NO: 118, and a second VL as set forth in SEQ ID NO: 120. 
     
     
         26 . A bispecific single chain antibody that comprises:
 a. a first VH CDR1 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 45;   b. a first VH CDR2 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 46;   c. a first VH CDR3 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 47;   d. a first VL CDR1 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 9;   e. a first VL CDR2 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 10;   f. a first VL CDR3 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 11;   g. a second VH CDR1 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 115;   h. a second VH CDR2 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 116;   i. a second VH CDR3 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 117;   j. a second VL CDR1 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 112;   k. a second VL CDR2 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 113; and   l. a second VL CDR3 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 114.   
     
     
         27 . A bispecific single chain antibody having the sequence is set forth in SEQ ID NO: 127 or SEQ ID NO: 129. 
     
     
         28 . A bispecific single chain antibody comprising any of SEQ ID NOs: 158-185 and further comprising SEQ ID NO: 122. 
     
     
         29 . An isolated antibody or antigen binding protein or fragment thereof which competes for binding with the antibody of  claim 1 . 
     
     
         30 . The antibody or antigen binding protein or fragment thereof of  claim 1 , wherein the antibody further comprises and IgG heavy chain constant domain and an IgG light chain constant domain. 
     
     
         31 . The antibody or antigen binding protein or fragment thereof of  claim 1 , wherein the antibody is a monoclonal antibody. 
     
     
         32 . The antibody or antigen binding protein or fragment thereof of  claim 1 , wherein the antibody is a chimeric antibody, a humanized antibody, or a fully human antibody. 
     
     
         33 . A sterile composition comprising the isolated antibody or or antigen binding protein or fragment thereof of any one of  claim 1 . 
     
     
         34 . The composition of  claim 33  further comprising a pharmaceutically acceptable carrier. 
     
     
         35 . An isolated nucleic acid encoding the antibody or antigen binding protein or fragment thereof of  claims 1 . 
     
     
         36 . A vector comprising the nucleic acid of  claim 35 . 
     
     
         37 . A host cell comprising the nucleic acid of  claim 35 . 
     
     
         38 . A host cell comprising the vector of  claim 36 . 
     
     
         39 . A method for producing an antibody or antigen binding protein or fragment thereof comprising culturing the host cell of  claim 37  under suitable conditions and recovering said antibody. 
     
     
         40 . A method for producing an antibody or antigen binding protein or fragment thereof comprising culturing the host cell of  claim 38  under suitable conditions and recovering said antibody. 
     
     
         41 . A method of inhibiting or reducing the growth of mesothelin expressing tumor cells in an animal, comprising administering to said animal a therapeutically effective dose of the antibody or antigen binding protein or fragment thereof of  claim 1 . 
     
     
         42 . A method of treating cancer in a subject in need thereof, comprising administering to said subject a therapeutically effective dose of the antibody or antigen binding protein or fragment thereof of  claim 1 . 
     
     
         43 . The method of  claim 41 , wherein said animal is human. 
     
     
         44 . A method of determining if a subject has mesothelin expressing tumor cells, comprising:
 a. contacting a tumor sample from the subject with the antibody or antigen binding protein or fragment thereof of  claim 1 ; and   b. detecting binding of the antibody or antigen binding protein or fragment thereof to the sample, wherein an increase in binding of the antibody or antigen binding protein or fragment thereof to the sample as compared to binding of the antibody or antigen binding protein or fragment thereof to a control sample identifies the subject as having mesothelin expressing tumor cells.   
     
     
         45 . The method of  claim 44 , wherein the isolated human monoclonal antibody or antigen binding protein or fragment thereof is directly labeled.

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