Patent application EP19172075A (EP), filed 2019-04-30
Publication number: EP3733714A1
Title: HER2-BINDING TETRAMERIC POLYPEPTIDES
Abstract: [0001]    The invention relates to a tetrameric polypeptide comprising a first polypeptide chain comprising a first VL antigen binding domain and a first CL constant domain, a second polypeptide chain comprising a first VH antigen binding domain, a first CH1 constant domain, a first CH2 constant domain and a first CH3 constant domain, a first ligand binding to a HER2 D4 epitope linked to the N-terminus of said first VL antigen binding domain or said first VH antigen binding domain by a first interdomain amino acid linker, a third polypeptide chain comprising a second VL antigen binding domain and a second CL constant domain, a fourth polypeptide chain comprising a second VH antigen binding domain, a second CH1 constant domain, a second CH2 constant domain and a second CH3 constant domain and a third ligand binding to a HER2 D4 epitope linked to the N-terminus of said second VL antigen binding domain or said second VH antigen binding domain by a second interdomain amino acid linker, wherein the VL antigen binding domains and the VH antigen binding domains together constitute a second ligand and a fourth ligand binding to a HER2 D1 epitope. The invention further relates to the tetrameric polypeptide for use in a method for the prevention or treatment of a malignant neoplastic disease, an isolated nucleic acid and a host cell for expression of the polypeptide and a method for obtaining the polypeptide.
IPC codes: A61K  39/    00            A I
A61P  35/    00            A I
C07K  16/    32            A I
C07K  16/    46            A I
Claims: number: 1
text: A tetrameric polypeptide comprising or consisting of
number: 2
text: The polypeptide according to claim 1, wherein
number: 3
text: The tetrameric polypeptide according to any one of the preceding claims, wherein said first CH2 constant domain and said first CH3 constant domain of said second polypeptide chain interact with, particularly are covalently linked with, said second CH2 constant domain and said second CH3 constant domain of said fourth polypeptide chain, such that a tetrameric polypeptide is formed.
number: 4
text: The tetrameric polypeptide according to any one of the preceding claims, wherein said second polypeptide chain comprises a first hinge region between said first CH1 constant domain and said first CH2 constant domain, and said fourth polypeptide chain comprises a second hinge region between said second CH1 constant domain and said second CH2 constant domain, wherein said first hinge region and said second hinge region mediate complex formation between said second polypeptide chain and said fourth polypeptide chain, particularly by at least one disulphide bond, such that a tetrameric polypeptide is formed.
number: 5
text: The polypeptide according to any one of the preceding claims, wherein said first ligand and/or said third ligand comprises or consists of a single-chain variable fragment polypeptide chain comprising an scFv heavy chain, an scFv linker chain, and an scFv light chain, wherein particularly
number: 6
text: The polypeptide according to claim 5, wherein said scFv linker chain comprises a peptide sequence characterized by a sequence identity of 70 % or more, particularly 80 % or more, more particularly 90 % or more, even more particularly 95 % or more, with SEQ ID No. 16, wherein most particularly said scFv linker chain comprises a peptide sequence identical to SEQ ID No. 16.
number: 7
text: The polypeptide according to any one of the preceding claims, wherein
number: 8
text: The polypeptide according to any one of the preceding claims, wherein
number: 9
text: The polypeptide according to any one of the preceding claims, wherein
number: 10
text: The polypeptide according to any one of the preceding claims, wherein
number: 11
text: The polypeptide according to any one of the preceding claims, wherein said first interdomain amino acid linker and/or said second interdomain amino acid linker consists of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 amino acids, and wherein said first interdomain amino acid linker and/or said second interdomain amino acid linker comprises or consists of amino acids G, A, J, S, T, P, C, V, M and E, particularly wherein said first interdomain amino acid linker and/or said second interdomain amino acid linker comprises or consists of amino acids G, S, A and T, more particularly wherein said first interdomain amino acid linker and/or said second interdomain amino acid linker is characterized by an amino acid sequence (GGGGS)n, with n being 1, 2, 3, 4 or 5 or said first interdomain amino acid linker and/or said second interdomain amino acid linker comprises or consists of a peptide sequence selected from one of SEQ ID No. 17, SEQ ID 55 to SQ ID 69 and SEQ ID 82 to SEQ ID 91 or a functional equivalent peptide sequence characterized by a sequence identity of at least 70%.
number: 12
text: The polypeptide according to any one of the claims 1 to 11 for use in a method for the prevention or treatment of a malignant neoplastic disease associated with expression of HER2.
number: 13
text: An isolated nucleic acid encoding at least one of the first polypeptide chain, the second polypeptide chain, the third polypeptide chain and the fourth polypeptide chain of the polypeptide according to any one of the claims 1 to 11.
number: 14
text: A host cell which is adapted to produce at least one of the first polypeptide chain, the second polypeptide chain, the third polypeptide chain and the fourth polypeptide chain of the polypeptide according to any one of the claims 1 to 11, wherein particularly the host cell comprises the isolated nucleic acid according to claim 13, such that the host cell is able to produce at least one of the first polypeptide chain, the second polypeptide chain, the third polypeptide chain and the fourth polypeptide chain of the polypeptide according to any one of the claims 1 to 11.
number: 15
text: A method for obtaining the polypeptide according to any one of the claims 1 to 11, wherein the method comprises culturing the host cell according to claim 14, so that at least one of the first polypeptide chain, the second polypeptide chain, the third polypeptide chain and the fourth polypeptide chain of the polypeptide according to any one of the claims 1 to 11 is produced.
Office action: search_report, dated 2020-11-04
Rejection reasons: inventive_step_epc_56
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ref_id: - VAHEH OGANESYAN ET AL, "Structural insights into the mechanism of action of a biparatopic anti-HER2 antibody", JOURNAL OF BIOLOGICAL CHEMISTRY, (20180418), vol. 293, no. 22, doi:10.1074/jbc.M117.818013, ISSN 0021-9258, pages 8439 - 8448, XP055633117 [Y] 1-15 * figure 1 *
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ref_type: npl
severity: obviousness
Final disposition: pending (2020-11-04)