US2017114151A1PendingUtilityA1

Multispecific and multivalent binding proteins and uses thereof

48
Assignee: MEDIMMUNE LLCPriority: Nov 7, 2011Filed: Aug 8, 2016Published: Apr 27, 2017
Est. expiryNov 7, 2031(~5.3 yrs left)· nominal 20-yr term from priority
Inventors:Nazzareno DimasiRyan FlemingBinyam BezabehChangshou GaoAntonio DigiandomenicoPaul WarrenerCharles K. StoverBret SellmanMladen TomichReena VarkeyPartha S. ChowdhuryRalph MinterSandrine GuillardSteven RustVignesh Venkatraman
C07K 2317/94C07K 16/2863C07K 16/468C07K 16/22C07K 2317/56C07K 2317/76C07K 2317/526C07K 2317/64C07K 2317/35C07K 2317/41C07K 16/1214C07K 2317/51C07K 16/00C07K 2317/55C07K 2317/53C07K 2317/524C07K 2317/31C07K 2317/73C07K 2317/66C07K 2317/622C07K 2317/52
48
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Claims

Abstract

The disclosure generally provides proteins that bind two epitopes (e.g., a first and a second epitope) and that are bivalent for binding to each of the first and second epitopes. The disclosure also provides compositions comprising such proteins, nucleic acid molecules encoding such proteins and methods of making and using such proteins.

Claims

exact text as granted — not AI-modified
We claim: 
     
         1 . A protein, comprising:
 a Fab arm that binds to a first epitope,   a binding domain (BD) that binds to a second epitope, and   an Fc region comprising C H 2 and C H 3 domains;   wherein the BD is interconnected to the Fab arm via a first polypeptide linker (L1) and to the Fc region via a second polypeptide linker (L2); and wherein the protein is bivalent for binding to each of the first and second epitopes.   
     
     
         2 . The protein of  claim 1 , wherein the L1 comprises 1-50 amino acid residues. 
     
     
         3 . The protein of  claim 1 , wherein the L2 comprises 1-50 amino acid residues. 
     
     
         4 . The protein of  claim 1 , wherein each of the L1 and the L2 comprises 1-50 amino acid residues. 
     
     
         5 . The protein of  claim 1 , wherein each of the L1 and the L2 comprises 15-30 amino acid residues. 
     
     
         6 . The protein of  claim 1 , wherein the L1 comprises a hinge portion and a linker portion. 
     
     
         7 . The protein of  claim 1 , wherein the L2 comprises a hinge portion and a linker portion. 
     
     
         8 . The protein of  claim 1 , wherein each of the L1 and the L2 comprises a hinge portion and a linker portion. 
     
     
         9 . The protein of  claim 1 , wherein the L1 comprises at least 5 amino acid residues of an antibody hinge region. 
     
     
         10 . The protein of  claim 1 , wherein the L2 comprises at least 5 amino acid residues of an antibody hinge region. 
     
     
         11 . The protein of  claim 1 , wherein the L1 comprises at least 7 amino acid residues of an antibody hinge region. 
     
     
         12 . The protein of  claim 1 , wherein the L2 comprises at least 7 amino acid residues of an antibody hinge region. 
     
     
         13 . The protein of  claim 1 , wherein the L2 comprises at least 12 amino acid residues of an antibody hinge region. 
     
     
         14 . The protein of  claim 1 , wherein the L1 comprises 8 amino acid residues of an antibody hinge region. 
     
     
         15 . The protein of  claim 1 , wherein the L2 comprises 15 amino acid residues of an antibody hinge region. 
     
     
         16 . The protein of  claim 1 , wherein each of the L1 and the L2 comprises all or part of an antibody hinge region or a modified antibody hinge region. 
     
     
         17 . The protein of  claim 1 , wherein the L1 comprises at least 5 amino acid residues of an antibody hinge region, and wherein the hinge region comprises an aspartic acid to glycine substitution at EU position 221. 
     
     
         18 . The protein of  claim 16 , wherein the hinge region comprises a substitution where a cysteine is replaced with another amino acid. 
     
     
         19 . The protein of  claim 1 , wherein the L2 comprises at least 5 amino acid residues of an antibody hinge region, and wherein the hinge region comprises a cysteine to valine substitution at EU position 220 
     
     
         20 . The protein  claim 1 , wherein the L1 comprises a linker portion comprising a Gly-Ser peptide. 
     
     
         21 . The protein of  claim 1 , wherein the L2 comprises a linker portion comprising a Gly-Ser peptide. 
     
     
         22 . The protein of  claim 1 , wherein each of the L1 and the L2 comprises a linker portion comprising a Gly-Ser peptide. 
     
     
         23 . The protein of  claim 22 , wherein the Gly-Ser peptide is of the formula (Gly 4 Ser)n, wherein n is a positive integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10. 
     
     
         24 . The protein of  claim 1 , wherein the L1 does not include a hinge portion. 
     
     
         25 . The protein of  claim 1 , wherein the L2 does not include a hinge portion. 
     
     
         26 . The protein of  claim 1 , wherein the L1 and the L2 do not include a hinge portion. 
     
     
         27 . The protein of  claim 1 , wherein the L1 comprises the amino acid sequence EPKSCDKT (SEQ ID NO:4). 
     
     
         28 . The protein of  claim 1 , wherein the L1 comprises the amino acid sequence EPKSCGKT (SEQ ID NO:6). 
     
     
         29 . The protein of  claim 1 , wherein the L1 comprises the amino acid sequence EPKSC (SEQ ID NO:38). 
     
     
         30 . The protein of any of  claims 1 - 23 ,  27 - 29 , wherein the L2 comprises the amino acid sequence EPKSVDKTHTCPPCP (SEQ ID NO: 12). 
     
     
         31 . The protein of any of  claims 1  or  27 - 29 , wherein the L2 comprises the amino acid sequence CPPCP (SEQ ID NO: 14). 
     
     
         32 . The protein of any of  claims 1  or  27 - 29 , wherein the L2 comprises the amino acid sequence DKTHTCPPCP (SEQ ID NO:40). 
     
     
         33 . The protein of  claim 1 , wherein the BD is selected from the group consisting of an scFv, a single domain antibody, a single chain diabody, an antibody mimetic, an antibody variable domain, and a receptor binding domain. 
     
     
         34 . The protein of  claim 33 , wherein the BD comprises an scFv. 
     
     
         35 . The protein of  claim 34 , wherein the scFv comprises a VH domain, a polypeptide linker and a VL domain. 
     
     
         36 . The protein of  claim 35 , wherein the Fab domain is interconnected via the L1 to an N-terminus of the VH domain of the scFv. 
     
     
         37 . The protein of  claim 35 , wherein the Fab domain is interconnected via the L1 to an N-terminus of the VL domain of the scFv. 
     
     
         38 . The protein of  claim 35 , wherein the Fc region is interconnected via the L2 to a C-terminus of the VH domain of the scFv. 
     
     
         39 . The protein of  claim 35 , wherein the Fc region is interconnected via the L2 to a C-terminus of the VL domain of the scFv. 
     
     
         40 . The protein of any of  claim 35 , wherein the VL domain of the scFv has a cysteine at Kabat position 100. 
     
     
         41 . The protein of any of  claim 35 , wherein the VH domain of the scFv has a cysteine at Kabat position 44. 
     
     
         42 . The protein of  claim 33 , wherein the antibody mimetic is selected from the group consisting of a minibody, a maxybody, an avimer, an Fn3 based protein scaffold, an ankyrin repeat, a VASP polypeptide, an avian pancreatic polypeptide (aPP), a Tetranectin, an affililin, a knottin, an SH3, a PDZ domain, a protein A domain, a lipocalin, a transferrin, and a kunitz domains. 
     
     
         43 . The protein of  claim 1 - 42 , wherein the Fc region is selected from the group consisting of an Fc region from an IgG1, IgG2, IgG3, IgG4, IgA, IgM, IgE, and IgD. 
     
     
         44 . The protein of  claim 43 , wherein the Fc region comprises a variant Fc region. 
     
     
         45 . The protein of  claim 43 , wherein the Fc region is aglycosylated. 
     
     
         46 . The protein of  claim 43 , wherein the Fc region is deglycosylated. 
     
     
         47 . The protein of  claim 43 , wherein the Fc region has reduced fucosylation or is afucosylated. 
     
     
         48 . The protein of any of  claim 44 , wherein the variant Fc region comprises a substitution at position 297. 
     
     
         49 . The protein of  claim 48 , wherein the substitution at position 297 is 297Q. 
     
     
         50 . The protein of  claim 43 , wherein the variant Fc region comprises a substitution at one or more of positions 239, 282, 289, 297, 312, 324, 330, 335, 337, 339, 356, 359, 361, 383, 384, 398, 400, 440, 422, and 442, as numbered by the EU index. 
     
     
         51 . The protein  claim 1 , wherein the CH1 domain of the Fab arm comprises a substitution at one or more of positions 131, 132, 134, 135, 136 and 139, as numbered by the EU index. 
     
     
         52 . The protein of  claim 50 , wherein substitution comprises a substitution to an amino acid chosen from cysteine, lysine, tyrosine, histidine, selenocysteine, and selenomethionine. 
     
     
         53 . The protein of  claim 52 , wherein the substitution is a cysteine. 
     
     
         54 . The protein of  claim 1 , wherein the protein comprises a chimeric heavy chain comprising the following polypeptide domains, from N-terminus to C-terminus
   VH1-CH1-L1-BD-L2-Fc;   wherein VH1 comprises the heavy chain variable domain of the Fab, CH1 comprises the heavy chain constant domain 1 of the Fab, L1 comprises the first linker polypeptide, BD comprises binding unit 2, L2 comprises the second linker polypeptide, and Fc comprises a C H 2 and a C H 3 domain.   
     
     
         55 . The protein of  claim 54 , wherein BD comprises an scFv. 
     
     
         56 . The protein of  claim 55 , wherein the scFv comprising, from N-terminus to C-terminus,
   VH2-polypeptide linker-VL2 or VL2-polypeptide linker-VH2;   wherein VH2 comprises the heavy chain variable domain of the scFv and VL2 comprises the light chain variable domain of the scFv.   
     
     
         57 . The protein of  claim 54 , wherein the L1 comprises a hinge portion and a linker portion. 
     
     
         58 . The protein of  claim 54 , wherein the L2 comprises a hinge portion and a linker portions. 
     
     
         59 . The protein of  claim 57 , wherein the L1 comprises, from N-terminus to C-terminus, a hinge portion and a linker portion. 
     
     
         60 . The protein of any of  claim 57 , wherein the L2 comprises, from N-terminus to C-terminus, a linker portion and a hinge portion. 
     
     
         61 . The protein of  claim 1 , wherein the first and second epitopes are different. 
     
     
         62 . The protein of  claim 1 , wherein the first and second epitopes are the same. 
     
     
         63 . The protein of  claim 1 , wherein the Fab arm and/or Fc region further comprise at least one binding unit. 
     
     
         64 . The protein of  claim 63 , wherein the at least one binding unit is interconnected to the Fab arm and/or Fc via a polypeptide linker. 
     
     
         65 . The protein of  claim 63 , wherein the at least one binding unit is interconnected at the N-terminal and/or C-terminal end of the chimeric heavy chain. 
     
     
         66 . The protein of  claim 63 , wherein the at least one binding unit is interconnected at the N-terminal and/or C-terminal end of the light chain. 
     
     
         67 . The protein of  claim 65 , wherein the at least one binding unit is interconnected at the N-terminal and/or C-terminal end of the heavy chain, and at least one binding unit is interconnected to the N-terminal and/or C-terminal end of the light chain. 
     
     
         68 . The protein of  claim 65 , wherein at least one binding unit is interconnected at the N-terminal and C-terminal end of the heavy chain, and/or at least one binding unit is interconnected to the N-terminal and C-terminal end of the light chain. 
     
     
         69 . The protein of  claim 65 , wherein at least one binding unit is interconnected at the N-terminal and C-terminal end of the heavy chain, and at least one binding unit is interconnected to the N-terminal and C-terminal end of the light chain. 
     
     
         70 . The protein of  claim 1 , wherein the protein further comprises at least one additional binding unit interconnected between the Fab arm and the Fc region. 
     
     
         71 . The protein of  claim 70 , wherein at least one additional binding unit is interconnected between L1 and the BD. 
     
     
         72 . The protein of  claim 70 , wherein at least one additional binding unit is interconnected between the BD and L2. 
     
     
         73 . The protein of  claim 71 , wherein at least one additional binding unit is interconnect to the BD by a polypeptide linker. 
     
     
         74 . The protein of  claim 63 , wherein each binding unit is selected from the group consisting of a Fab domain, an scFv, a single domain antibody, a single chain diabody, an antibody mimetic, an antibody variable domain, and a receptor binding domain. 
     
     
         75 . The protein of  claim 63 , wherein the binding units each bind different epitopes. 
     
     
         76 . The protein of  claim 63 , wherein two or more binding units each bind the same epitopes. 
     
     
         77 . The protein of  claim 63 , wherein the at least one binding units do not bind the first epitope and/or the second epitope. 
     
     
         78 . The protein of  claim 63 , wherein the at least one binding units do not bind the first epitope and do not bind the second epitope. 
     
     
         79 . A composition comprising the protein  claim 1  formulated in a pharmaceutically acceptable carrier. 
     
     
         80 . A nucleic acid molecule comprising a nucleotide sequence encoding the protein of  claim 1 . 
     
     
         81 . A nucleic acid composition comprising
 a first nucleic acid molecule comprising a first nucleotide sequence and   a second nucleic acid molecule comprising a second nucleotide sequence;   wherein the protein of  claim 1  is encoded by the first and second nucleic acid molecules.   
     
     
         82 . A vector comprising the nucleic acid of  claim 80  or  81 . 
     
     
         83 . A host cell comprising the vector of  claim 82 .

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