US2018201692A1PendingUtilityA1

Anti-her2 antibody variants

65
Assignee: GENENTECH INCPriority: Apr 10, 2002Filed: Oct 10, 2017Published: Jul 19, 2018
Est. expiryApr 10, 2022(expired)· nominal 20-yr term from priority
Inventors:Henry B. LowmanResi B. GerstnerPaul Carter
C07K 2317/55C07K 16/32C07K 2317/24A61P 35/02A61J 1/00C07K 2317/21A61J 1/18C07K 16/3015C07K 2317/54C07K 2317/92A61P 35/00A61J 2205/30C07K 2317/56
65
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Claims

Abstract

The present invention concerns novel antibody variants, particularly anti-HER2 antibody variants having substitutions at positions within the variable domains of the heavy and light chains

Claims

exact text as granted — not AI-modified
1 . A polypeptide which comprises an antibody light chain variable domain comprising the hypervariable regions of SEQ ID NO: 1 wherein one or more amino acids selected from the group consisting of Q27(V L ); D28(V L ), N30(V L ), T31(V L) , A32(V L ), Y49(V L ), F53(V L ), Y55(V L ), R66(V L ), H91(V L ), Y92 (V L ), and T94(V L ), numbered according to the Kabat numbering system, are substituted with any amino acid other than alanine. 
     
     
         2 . The polypeptide of  claim 1 , wherein. the hypervariable regions of SEQ ID NO: 1 comprise amino acid substitutions at one or more positions selected from the group consisting of N30(V L) , F53(V L) , Y55(V L ), H91(V L) , Y92(V L ), and T94(V L ,). 
     
     
         3 . The polypeptide of claim I wherein the hypervariable regions of SEQ ID NO: 1 comprise one or more amino acid substitutions selected from the group consisting of D28(V L )Q; D28(V L )G; N30(V L )S; T31(V L )S; A32(V L )G; Y49(V L )W, Y49(V L )D, 49(V L )V; F53(V L )W. F53(V L )V, F53(V L )Q, Y55(V L )W, R66(V L )N, H91(V L )F, H91(V L )Y, Y92(V L )W, and T94(V L )S. 
     
     
         4 . The polypeptide of  claim 3  wherein the hypervariable regions of SEQ ID NO: 1 comprise one or more amino acid substitutions selected from the group consisting of D28(V L )Q; D28(V L )G; N30(V L )S; T3I(V L )S; A32(V L )G; Y49(V L )W, Y49(V L )D, Y49(V L )V; F53(V L )W, F53(V L )V, F53(V L )Q, Y55(V L )W, R66(V L )N, H9I(V L )F, H91(V L )Y, and Y92(V L )W. 
     
     
         5 . The polypeptide of  claim 4  wherein the hypervariable regions of SEQ ID NO: I comprise one or more amino acid substitutions selected from the group consisting of Y49(V L )D, F53(V L )W, and Y55(V L )W. 
     
     
         6 . The polypeptide of  claim 5  comprising two or three or said amino acid substitutions. 
     
     
         7 . The polypeptide of  claim 6  comprising all three of said amino acid substitutions. 
     
     
         8 . The polypeptide of  claim 3 , wherein the hypervariable regions of SEQ ID NO: 1 comprise one or more amino acid substitutions selected from the group consisting of N30(V L )S, F53(V L )W, Y55(V L )W, H91(V L ) F, Y92(V L )W and T94(V L )S. 
     
     
         9 . The polypeptide of  claim 8 , wherein N30(V L ) substituted with S, H91(V L ), is substituted with F, and Y92(V L ) is substituted with W. 
     
     
         10 . The polypeptide of  claim 1  which is an antibody. 
     
     
         11 . The polypeptide of  claim 10 , which is a humanized antibody. 
     
     
         12 . The polypeptide of  claim 10 , which is a human antibody. 
     
     
         13 . The polypeptide of  claim 10 , which is an antibody fragment selected from the group consisting of Fv, Fab, Fab′ and F(ab′) 2  fragments. 
     
     
         14 . A polypeptide which comprises an antibody heavy chain variable domain comprising the hypervariable regions of SEQ ID NO: 2 wherein one or more amino acids selected from the group consisting of W95(V II ), D98(V II ), F100(V II ), Y100a(V II ), and Y102(V H ), numbered according to the Kabat numbering system, are substituted with any amino acid other than alanine. 
     
     
         15 . The polypeptide of  claim 14 , wherein the hypes-variable regions of SEQ ID NO: 2 comprise one or more amino acid substitutions selected from the group consisting of W95(V H )Y, D98(V H )W, D98(V H )R, D98(V H )K, D98(V H )H, F100(V H )P, F100(V H )L, F100(V H )M, Y100(V H )F, Y102(V H )V, Y102(V H )K, and Y102(V H )L. 
     
     
         16 . The polypeptide of  claim 15  wherein the hypervariable regions of SEQ ID NO: 2 comprise one or more amino acid substitutions selected from the group consisting of, D98(V H )W, Y100a(V H )F, and Y102(V H )V. 
     
     
         17 . The polypeptide of  claim 15  wherein the hypervariable regions of SEQ ID NO: 2 comprise one or two amino acid substitutions selected from the group consisting of F100(V H )P and Y102(V H ) K. 
     
     
         18 . The polypeptide of  claim 17  comprising the amino acid substitutions F100(V H )P and Y102(V H )K. 
     
     
         19 . The polypeptide of  claim 15  wherein the hypervariable regions of SEQ ID NO: 2 comprise one or two amino acid substitutions selected from the group consisting of FI00(V H )P and V102(V H )L. 
     
     
         20 . The polypeptide of  claim 19  comprising the amino acid substitutions of F100(V H )P and Y102(V H )L. 
     
     
         21 . The polypeptide of  claim 14 , which is an antibody. 
     
     
         22 . The polypeptide  claim 21 , which is a humanized antibody, 
     
     
         23 . The polypeptide of  claim 21 , which is a human antibody. 
     
     
         24 . The polypeptide of  claim 21 , which is an antibody fragment selected from the group consisting of Fv, Fab, F(ab′) 2  and F(ab′) 2  fragments. 
     
     
         25 . An antibody that is capable of binding to the extracellular domain of HER2 which comprises the hypervariable regions of SEQ ID NO: 1 wherein one or more amino acids selected from the group consisting of Q27(V L ), D28(V L ), N30(V L ), T31(V L ), A32(V L ), Y49(V L ), F53(V L ), F55(V L ), R66(V L ), H91(V L ) and T94(V L ), numbered according to the Kabat numbering system, are substituted with any amino acid other than alanine. 
     
     
         26 . The antibody of  claim 25  wherein one or more amino acids selected from the group consisting of N30(V L ), F53(V L ), Y55(V L ), H91(V L ), Y92(V L ), and T94(V L ), numbered according to the Kabat numbering system, are substituted with any amino acid other than alanine. 
     
     
         27 . The antibody of  claim 25  wherein the hypervariable regions of SEQ ID NO: 1 comprise one or more amino acid substitutions selected from the group consisting of D28(V L )Q; D28(V L )G; N30(V L )S; T3I(V L )S; A32(V L )G; Y49(V L )W, Y49(V L )D, Y49(V L )V; F53(V L )W, F53(V L )V, F53(V L )Q, Y55(V L )W, R66(V L )N, H91(V L )F, H91(V L )Y, Y92(V L )W, and T94(V L )S. 
     
     
         28 . The antibody of  claim 27  wherein the hypervariable regions of SEQ ID NO: 1 comprise one or more amino acid substitutions selected from the group consisting of D28(V L )Q; D28(V L )G; N30(V L )S; T31(V L )S; A32(V L )G; Y49(V L )W, Y49(V L )D, Y49(V L )V; F53(V L ) W, F53(V L )V, F53(V L )Q, Y55(V L )W, R66(V L )N, H91(V L )F, H91(V L )Y, and Y92(V L )W. 
     
     
         29 . The antibody of  claim 28  wherein the hypervariable regions of SEQ ID NO: 1 comprise one or more amino acid substitutions selected from the group consisting of Y49(V L )D, F53(V L )W, and Y55(V L )W. 
     
     
         30 . The antibody of  claim 29  comprising two or three or said amino acid substitutions. 
     
     
         31 . The antibody of  claim 30  comprising all three of said amino acid substitutions. 
     
     
         32 . The antibody of  claim 26 , wherein the hypervariable regions of SEQ ID NO: 1 comprise one or more amino acid substitutions selected from the group consisting of N30(V L )S, F53(V L )W, Y55(V L )W, H91(V L )F, Y92(V L )W, T94(V L )S. 
     
     
         33 . The antibody of  claim 32 , wherein N30(V I ) is substituted with S, H91(V I ) is substituted with F, and Y92(V L ) is substituted with W. 
     
     
         34 . The antibody of  claim 25 , which is a humanized antibody. 
     
     
         35 . The antibody of  claim 25 , which is a human antibody. 
     
     
         36 . The antibody of  claim 25 , which is a antibody fragment selected from the group consisting of Fv, Fab, Fab′ and F(ab′) 2  fragments. 
     
     
         37 . An antibody that is capable of binding to the extracellular domain of HER2, which comprises an antibody heavy chain variable domain comprising the hypervariable regions of SEQ ID NO: 2 wherein one or more amino acids selected from the group consisting of W95(V H ), D98(V H ), F100(V H ), Y100a(V H ), and Y102(V H ), numbered according to the Kabat numbering system, are substituted with any amino acid other than alanine. 
     
     
         38 . The antibody of  claim 37  wherein the hypervariable regions of SEQ ID NO: 2 comprise one or more amino acid substitutions selected from the group consisting of W95(V H )Y, D98(V H )W, D98(V H )R, D98(V H )K, D98(V H )H, FI00(V H )P, F100(V H )L, F100(V H )M, 100a(V H )F, Y102(V H )V, Y102(V H )K, and Y102(V H )L. 
     
     
         39 . The antibody of  claim 38  wherein the hypervariable regions of SEQ ID NO: 2 comprise one or more amino acid substitutions selected from the group consisting of D98(V H )W, Y100a(V H )F, and Y102(V H )V. 
     
     
         40 . The antibody of  claim 38  wherein the hypervariable regions of SEQ ID NO: 2 comprise one or more amino acid substitutions selected from the group consisting of F100(V H )P and Y102(V H )K. 
     
     
         41 . The polypeptide of  claim 40  comprising the amino acid substitutions F100(V II )P and Y102(V II )K. 
     
     
         42 . The antibody of  claim 20 , which is a humanized antibody. 
     
     
         43 . The antibody of  claim 37 , which is a human antibody. 
     
     
         44 . The antibody of  claim 37 , which is an antibody fragment selected from the group consisting of Fv, Fab, Fab′ and F(ab′) 2  fragments. 
     
     
         45 . An antibody that is capable of binding to the extracellular domain of HER2, which comprises the hypervariable regions of SEQ ID NOs: 1 and 2 wherein one or more amino acids selected from the group consisting of D28(V L ), N30(V L ), T31(V L ), A32(V L ), Y49(V L ), F53(V L ), Y55(V L ), R66(V L ), H91(V L ), Y92(V L ), T94(V L ), W95(V H ), D98(V H ), F100(V H ); Y100a(V H ), and Y102(V H ), numbered according to the Rabat numbering system, are substituted with any amino acid other than alanine. 
     
     
         46 . The antibody of  claim 45 , wherein the hypervariable regions of SEQ ID NOs: 1 and 2 comprise one or more amino acid substitutions selected from the group consisting of N30(V L )S, F53(V L )W, Y55(V L )W, H91(V L )F, Y92(V L )W, T94(V L )S, D98(V H )W, Y100a(V H )F, and Y102(V H )V. 
     
     
         47 . The antibody of  claim 46 , wherein N30(V L ) is substituted with S, H91(V L ) is substituted with F, Y92(V L ) is substituted with W, T94(V L ) is substituted with S, D98(V H ) is substituted with W, Y100a(V H ) is substituted with F, and Y102(V H ) is substituted with V. 
     
     
         48 . The antibody of  claim 46 , wherein D98(V H ) is substituted with W. 
     
     
         49 . The antibody of  claim 45 , wherein the hypervariable regions of SEQ ID NOs 1 and 2 comprise one or more amino acid substitutions selected from the group consisting of D28(V L )Q; D28(V L )G; N30(V L )S; T31(V L )S; A32(V L )G; Y49(V L )W, Y49(V L )D, Y49(V L )V; F53(V L )W, F53(V L )V, F53(V L )Q, Y55(V L )W, R66(V L )N, H91(V L )F, H91(V L )Y, Y92(V L )W, T94(V L )S, W95(V H )Y, D98(V H )W, D98(V H )R, D98(V H )K, D98(V H )H, F100(V H )P, F100(V H )L, F100(V H )M, Y100a(V II )F, Y102(V II )V, Y102(V II )K, and Y102(V II ) L. 
     
     
         50 . The antibody of  claim 45 , wherein the hypervariable regions of SEQ ID NOs 1 and 2 comprise one or more amino acid substitutions selected from the group consisting of Y49(V I )D, F53(V I )W, Y55(V I )W, D98(V II )W, F100(V II )P, and Y102(V H )L. 
     
     
         51 . The antibody of  claim 50  wherein the hypervariable regions of SEQ ID NOs: 1 and 2 comprise the following substitutions: Y49(V I )D, F53(V I )W, Y55(V L )W, F100(V H )P, and Y102(V H )L. 
     
     
         52 . The antibody of  claim 51  wherein the hypervariable regions of SEQ ID NO 2 further comprise the substitution D98(V H )W. 
     
     
         53 . The antibody of  claim 50  wherein the hypervariable regions of SEQ ID NOs: 1 and 2 comprise the following substitutions: Y49(V L )D, F53(V L )W, Y55(V L )W, F100(V L )P, and Y102(V H )K. 
     
     
         54 . The antibody of  claim 53  wherein the hypervariable regions of SEQ ID NO 2 further comprise the substitution D98(V H )W. 
     
     
         55 . The antibody of  claim 45 , wherein the binding affinity of the antibody for the HER2 extracellular domain is at least about three-fold better than the binding affinity of humanized monoclonal antibody 4D5-8 for the HER2 extracellular domain. 
     
     
         56 . The antibody of  claim 45 , which is a humanized antibody. 
     
     
         57 . The antibody of  claim 45 , which is a human antibody. 
     
     
         58 . The antibody of  claim 45 , which is an antibody fragment selected from the group consisting of Fv, Fab, Fab′ and F(ab′) 2  fragments. 
     
     
         59 . An antibody that is capable of binding to the extracellular domain of HER2 which comprises the light chain variable domain of SEQ ID NO: 1 wherein one or more amino acids selected from the group consisting of Q27(V L ), N30(V L ), Y49(V L ), F53(V L ), Y55(V L ), H91(V L ), Y92(V L ), and T94(V L ), numbered according to the Kabat numbering system, are substituted with any amino acid other than alanine. 
     
     
         60 . The antibody of  claim 59 , wherein the light chain variable domain of SEQ ID NO: 1 comprises one or more amino acid substitutions selected from the group consisting of N30(V L )S, Y49(V L )F, Y49(V L )W, F53(V L )W, Y55(V L )W, H91(V L )F, Y92(V L )W, and T94(V L )S. 
     
     
         61 . The antibody of  claim 60 , wherein N30(V I ) is substituted with S, H91(V I ) is substituted with F, and Y92(V L ) is substituted with W. 
     
     
         62 . A humanized anti-HER2 antibody 4D5-8, comprising one or more amino acid substitutions selected from the group consisting of N30(V L )S, Y49(V L )F, V49(V L )W, F53(V L )W, Y55(V L )W, H91(V L )F, Y92(V L )W, T94(V L )S, F100(V L )W, D98(V H )W, 100a(V H )F, and Y102(V H )V, numbered according to the Kabat numbering system. 
     
     
         63 . A humanized anti-HER2 antibody 4D5-8 which comprises one or more amino acid substitutions selected from the group consisting of Y49(V L )D, F53(V L )W, Y55(V L )W, F100(V H )P, Y102(V H )K, and Y102(V H )L. 
     
     
         64 . The antibody of  claim 63  further comprising the amino acid substitution D98(V H )W. 
     
     
         65 . The antibody of  claim 62  comprising the one or more of the amino acid substitutions selected from the group consisting of Y49(V L )D, F53(V L )W, and Y55(V L )W. 
     
     
         66 . The antibody of  claim 62  comprising one or more of the amino acid substitutions selected from the group consisting of F100(V H )P, Y102(V H )K, and Y102(V H )L. 
     
     
         67 . The antibody of  claim 64  comprising the following amino acid substitutions: Y49(V L )D, F53(V L )W, Y55(V L )W, F100(V H )P, and Y102(V H )K. 
     
     
         68 . The antibody of  claim 64  comprising the following amino acid substitutions: Y49(V L )D, F53(V L )W, Y55(V L )W, F100(V L )P, and Y102(V L )L. 
     
     
         69 . An article of manufacture comprising a container, a composition contained therein, and a package insert or label indicating that the composition can be used to treat cancer characterized by the overexpression of HER2, wherein the composition comprises the antibody of  claim 60  or  61 . 
     
     
         70 . The article of manufacture of  claim 69 , wherein the cancer is breast cancer. 
     
     
         71 . An antibody variant of a parent antibody which binds HER2, comprising an amino acid substitution at position 98 of a heavy chain variable domain thereof, and wherein the binding affinity of the antibody variant for HER2 is better than the binding affinity of the parent antibody for HER2. 
     
     
         72 . The antibody variant of  claim 71 , wherein the amino acid at position 98 is substituted with W. 
     
     
         73 . The antibody variant of  claim 70 , wherein the parent antibody is a humanized antibody. 
     
     
         74 . A method for isolating high-affinity variants of a humanized anti-HER2 antibody, comprising:
 (a) producing anti-HER2 variants with substitutions at one or more amino acids selected from the group consisting Q27(V I ), D28(V I ), N30(V I ), T31(V I ), A32(V I ), Y49(V I ), F53(V L ), Y55(V L ), R66(V L ), H91(V L ), Y92(V L ), T94(V L ), W95(V H ), D98(V H ), F100(V H ), Y100a(V H ), and Y102(V H ), within the hypervariable regions of SEQ ID NOs: 1 and 2, wherein numbering is according to the Kabat numbering system;   (b) measuring binding affinities of the variants produced in (a) for HER2 extracellular domain; and   (c) selecting for high-affinity variant.

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