WO2023277113A1 - Ｈｅｇ１タンパク質に結合するヒト化抗体 - Google Patents

Ｈｅｇ１タンパク質に結合するヒト化抗体 Download PDF

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WO2023277113A1
WO2023277113A1 PCT/JP2022/026140 JP2022026140W WO2023277113A1 WO 2023277113 A1 WO2023277113 A1 WO 2023277113A1 JP 2022026140 W JP2022026140 W JP 2022026140W WO 2023277113 A1 WO2023277113 A1 WO 2023277113A1
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amino acid
acid sequence
set forth
sequence set
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French (fr)
Japanese (ja)
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祥太郎 辻
浩三 今井
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University of Tokyo NUC
Kanagawa Prefectural Hospital Organization
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University of Tokyo NUC
Kanagawa Prefectural Hospital Organization
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Priority to JP2023532041A priority patent/JPWO2023277113A1/ja
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/567—Framework region [FR]

Definitions

  • the present disclosure relates to humanized antibodies that bind to HEG1 protein.
  • Malignant mesothelioma is a disease that has become a major social problem as a malignant tumor that is mainly caused by exposure to asbestos. Early detection is difficult, and it is positioned as one of malignant tumors with poor prognosis. Malignant mesothelioma may be pathologically similar to metastatic adenocarcinoma, sarcoma, and benign proliferation of reactive mesothelial cells, and is often difficult to differentiate pathologically. In addition, it is not uncommon to have difficulty in diagnosing various histological types such as epithelial type and sarcoma type.
  • Patent Document 1 discloses that mesothelioma can be detected with high sensitivity and specificity by reacting a mouse antibody that binds to HEG1 protein with mesothelioma tissue.
  • the present disclosure provides humanized antibodies that bind to HEG1 protein.
  • Humanized antibodies are suitable for pharmaceutical use.
  • an antibody or an antigen-binding fragment thereof is a humanized antibody capable of binding to the human HEG1 protein expressed on mesothelioma cells;
  • the antibody has a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence set forth in SEQ ID NO:37, a heavy chain CDR2 having the amino acid sequence set forth in SEQ ID NO:43, and a heavy chain CDR3 having the amino acid sequence set forth in SEQ ID NO:51.
  • an antibody or antigen-binding fragment thereof comprising: [2] The antibody or antigen-binding fragment thereof according to [1] above, Heavy chain variable region where the antibody comprises heavy chain CDR1 having the amino acid sequence set forth in SEQ ID NO:37, heavy chain CDR2 having the amino acid sequence set forth in SEQ ID NO:43, and heavy chain CDR3 having the amino acid sequence set forth in SEQ ID NO:51 and a light chain variable region comprising a light chain CDR1 having the amino acid sequence set forth in SEQ ID NO:63, a light chain CDR2 having the amino acid sequence set forth in SEQ ID NO:75, and a light chain CDR3 having the amino acid sequence set forth in SEQ ID NO:82 An antibody or antigen-binding fragment thereof, comprising: [2] The antibody or antigen-binding fragment thereof according to [1] above, Heavy chain variable region where the antibody comprises heavy chain CDR1 having the amino acid sequence set forth in SEQ ID NO:37, heavy chain CDR2 having the amino acid sequence set forth in SEQ ID
  • the heavy chain variable region has the heavy chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 104, the heavy chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 105, and the heavy chain having the amino acid sequence set forth in SEQ ID NO: 106. including CDR3;
  • the light chain variable region comprises a light chain CDR1 having the amino acid sequence set forth in SEQ ID NO:149, a light chain CDR2 having the amino acid sequence set forth in SEQ ID NO:150, and a light chain CDR3 having the amino acid sequence set forth in SEQ ID NO:151 ,
  • the antibody or antigen-binding fragment thereof according to any one of [1] to [5] above.
  • the heavy chain variable region comprises framework region 1 having the amino acid sequence set forth in SEQ ID NO: 32, framework region 2 having the amino acid sequence set forth in SEQ ID NO: 40, and frame having the amino acid sequence set forth in SEQ ID NO: 46.
  • the antibody or antigen-binding fragment thereof according to any one of [1] to [6] above, which has work region 3 and framework region 4 having the amino acid sequence set forth in SEQ ID NO:54.
  • the light chain variable region comprises framework region 1 having the amino acid sequence set forth in SEQ ID NO:57, framework region 2 having the amino acid sequence set forth in SEQ ID NO:72, and frame having the amino acid sequence set forth in SEQ ID NO:79.
  • the antibody or antigen-binding fragment thereof according to any one of [1] to [7] above, which has work region 3 and framework region 4 having the amino acid sequence set forth in SEQ ID NO:86.
  • the heavy chain variable region has an amino acid sequence selected from the group consisting of SEQ ID NOS: 1-6, 8, and 9;
  • the light chain variable region has an amino acid sequence selected from the group consisting of SEQ ID NOS: 10, 12-15, 17-21, and 29-31;
  • the antibody or antigen-binding fragment thereof according to any one of [1] to [8] above.
  • a composition for use in targeting HEG1 protein expressed in mesothelioma comprising the antibody or antigen-binding fragment thereof.
  • Use of the antibody or antigen-binding fragment thereof in the manufacture of a composition for use in targeting HEG1 protein expressed in mesothelioma Use of the antibody or antigen-binding fragment thereof in the manufacture of a composition for use in targeting HEG1 protein expressed in mesothelioma.
  • a method of targeting HEG1 protein expressed in mesothelioma in a subject comprising administering to the subject an effective amount of a composition comprising the antibody or antigen-binding fragment thereof.
  • FIG. 1 shows the HEG1-binding activity of a humanized antibody comprising a combination of a humanized heavy chain variable region and a humanized light chain variable region.
  • the heavy and light chain information of the antibody used is attached to each bar.
  • Activity is compared to a murine antibody (parental antibody) having a murine heavy chain variable region (xiH) and a murine light chain variable region (xiL).
  • FIG. 2 shows the HEG1-binding activity of humanized antibodies comprising combinations of humanized heavy chain variable regions and humanized light chain variable regions.
  • the heavy and light chain information of the antibody used is attached to each bar. (-) indicates background in the absence of antibody.
  • FIG. 1 shows the HEG1-binding activity of a humanized antibody comprising a combination of a humanized heavy chain variable region and a humanized light chain variable region.
  • the heavy and light chain information of the antibody used is attached to each bar.
  • (-) indicates background in the absence of antibody.
  • FIG. 3 shows the HEG1-binding activity of humanized antibodies comprising combinations of humanized heavy chain variable regions and humanized light chain variable regions. The heavy and light chain information of the antibody used is attached to each bar.
  • FIG. 4 shows the binding activity to HEG1 of a humanized antibody comprising a combination of a humanized heavy chain variable region and a humanized light chain variable region. The heavy and light chain information of the antibody used is attached to each bar.
  • FIG. 5 shows the HEG1-binding activity of humanized antibodies comprising combinations of humanized heavy chain variable regions and humanized light chain variable regions. The heavy and light chain information of the antibody used is attached to each bar.
  • FIG. 6 shows the binding activity to HEG1 of humanized antibodies comprising combinations of humanized heavy chain variable regions and humanized light chain variable regions.
  • FIG. 7 shows the effect of signal peptides on the production of each humanized antibody.
  • FIG. 8 shows the results of SDS-PAGE of each antibody purified from the culture supernatant after expressing each heavy chain and light chain in a CHO cell line.
  • FIG. 9 shows the results of Biacore measurement of the affinity of each antibody of purified humanized SKM9-2 to the synthetic sugar epitope in the left column, and the mesothelium of each purified humanized SKM9-2 antibody in the right column. This figure shows the results of measurement of binding to tumor cell line NCI-H226 by flow cytometry.
  • a "subject” can be a mammal, e.g., primates such as humans, marmosets, and chimpanzees, laboratory animals such as rats, mice, rabbits, pigs, cows, horses, sheep, goats, and the like. and domestic animals such as dogs and cats, preferably humans. More preferably, it may be a "cancer patient” suffering from or at risk of a tumor or cancer. More preferably, the subject may be a subject suffering from or potentially suffering from mesothelioma. "Patient” means a subject suffering from cancer, preferably, but not limited to, a human.
  • the term "antibody” refers to an immunoglobulin, a protein having a structure in which two heavy chains (H chains) and two light chains (L chains) stabilized by disulfide bonds are associated.
  • the heavy chain consists of a heavy chain variable region VH, heavy chain constant regions CH1, CH2, CH3, and a hinge region located between CH1 and CH2, and the light chain consists of a light chain variable region VL and a light chain constant region CL.
  • a variable region fragment (Fv) consisting of VH and VL is a region that directly participates in antigen binding and imparts diversity to antibodies.
  • the antigen-binding region consisting of VL, CL, VH and CH1 is called the Fab region, and the region consisting of the hinge region, CH2 and CH3 is called the Fc region.
  • the regions that directly contact the antigen undergo particularly large changes and are called complementarity-determining regions (CDRs).
  • CDRs complementarity-determining regions
  • a portion other than the CDRs with relatively few mutations is called a framework region (FR).
  • FR framework region
  • the light chain and heavy chain variable regions each have three CDRs, which are referred to as heavy chain CDRs 1-3 and light chain CDRs 1-3 in order from the N-terminus. Each CDR is integrated into framework regions.
  • the heavy chain variable region of the antibody consists of, from the N-terminal side to the C-terminal side, heavy chain framework region 1, heavy chain CDR1, heavy chain framework region 2, heavy chain CDR2, heavy chain framework region 3, heavy chain It has CDR3, and heavy chain framework region 4, in that order.
  • the light chain variable region of the antibody consists of, from the N-terminal side to the C-terminal side, light chain framework region 1, light chain CDR1, light chain framework region 2, light chain CDR2, light chain framework region 3, light chain It has CDR3, and light chain framework region 4, in that order.
  • Antibodies can be recombinant proteins (recombinant antibodies) and can be produced in animal cells, such as Chinese hamster ovary cells (CHO cells).
  • the origin of the antibody is not particularly limited, but examples thereof include non-human animal antibodies, non-human mammal antibodies (eg, mouse antibodies, rat antibodies, camel antibodies), and human antibodies.
  • Antibodies may also be chimeric, humanized, and fully humanized antibodies.
  • Antibodies may be polyclonal antibodies or monoclonal antibodies, preferably monoclonal antibodies.
  • a "chimeric antibody” is an antibody in which heavy and light chain constant regions of different species are linked to heavy and light chain variable regions, respectively.
  • a humanized antibody refers to an antibody in which the corresponding positions of a human antibody are substituted with an amino acid sequence characteristic of a non-human antibody, for example, the heavy chain CDRs 1 to 3 of an antibody produced by immunizing a mouse or rat.
  • Humanized antibodies may also include human chimeric antibodies.
  • a “human chimeric antibody” is a non-human antibody in which the constant region of the non-human antibody is replaced with the constant region of a human antibody. Alternatively, the antibody may be a bispecific antibody.
  • Antibodies can be isolated antibodies or purified antibodies. Antibodies can be, for example, IgG. Antibodies can be, for example, IgG1, IgG2 (eg, IgG2a and IgG2b), IgG3, or IgG4.
  • variable regions of immunoglobulin chains consist of relatively conserved framework regions (FR) joined by three hypervariable regions (more often called “complementarity determining regions” or CDRs). generally exhibit the same overall structure, including
  • the CDRs from the two chains of each heavy/light chain pair described above are represented by framework regions to form structures that specifically bind to specific epitopes on target proteins (e.g., PCSK9).
  • target proteins e.g., PCSK9
  • FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4 parallel to From N-terminus to C-terminus, both naturally occurring light and heavy chain variable regions typically conform to the following order of these elements.
  • a numbering system has been devised to assign numbers to the amino acids that occupy positions in each of these domains.
  • antigen-binding fragment refers to a portion of an antibody that retains antigen-binding.
  • Antigen-binding fragments may comprise the heavy chain variable region or the light chain variable region or both of the antibodies of this disclosure.
  • Antigen-binding fragments may be chimerized or humanized.
  • Antigen-binding fragments include, for example, Fab, Fab', F(ab') 2 and Fv.
  • Antibody-binding fragments also include recombinantly produced conjugates or functional equivalents (e.g., scFv (single-chain Fv), diabodies, scDb, tandem scFv, leucine zipper, sc(Fv) 2 ( other antibody portions) in the form of single-chain (Fv) 2 )).
  • scFv single-chain Fv
  • diabodies e.g., diabodies
  • scDb tandem scFv
  • leucine zipper e.g., antigen-binding fragment of an antibody
  • Such an antigen-binding fragment of an antibody is not particularly limited, but can be obtained, for example, by treating an antibody with an enzyme. For example, papain digestion of antibodies can yield Fabs. Alternatively, the antibody can be digested with pepsin to give F(ab') 2 , which can be further reduced to give Fab'. Antigen-binding fragments of such antibodies can be used herein.
  • VL and VH can be joined by an artificial polypeptide linker to maintain the same antigen specificity as the original antibody.
  • VL and VH can be linked in the order of VH and VL or VL and VH from the N-terminal side.
  • a linker can have a length on the order of 10-25 amino acids.
  • the linker may be rich in glycine and may contain amino acids such as serine and threonine for the purpose of increasing water solubility.
  • HEG1 protein is a protein expressed in the membrane of mesothelioma cells (WO2017/141604). According to WO2017/141604, HEG1 protein is considered to be glycosylated on the membrane of mesothelioma cells.
  • the sugar chain modification includes O-type sugar chain modification. Said glycosylation is sialylated. Said glycosylation may comprise ⁇ 2,3 sialylation. Said glycomodification is believed to be mesothelioma specific. Therefore, according to WO2017/141604, mesothelioma cells can be detected with an antibody that binds to the HEG1 protein having this sugar modification.
  • Human HEG1 protein includes a protein having the nucleic acid sequence and amino acid sequence encoded thereby deposited in the National Center for Biotechnology Information (NCBI) as NM_020733.1. From the results of gene ontology analysis, in the HEG1 protein, the signal peptide portion is a domain corresponding to positions 1 to 29 of the amino acid sequence, and the extracellular domain is a domain corresponding to positions 30 to 1248 of the amino acid sequence. , the transmembrane domain is predicted to be the domain corresponding to positions 1249-1269 of the above amino acid sequence, and the intracellular domain is predicted to be the domain corresponding to positions 1270-1381 of the above amino acid sequence.
  • NCBI National Center for Biotechnology Information
  • HEG1 proteins can also include proteins having amino acid sequences that are 90% or more, 95% or more, 98% or more, or 99% or more homologous to the above amino acid sequences.
  • the HEG1 protein may contain one or more amino acid substitutions, insertions, additions and/or deletions in the amino acid sequences represented by the above amino acid sequences.
  • amino acid sequences are represented by single-letter codes. That is, A represents alanine, R represents arginine, N represents asparagine, D represents aspartic acid, C represents cysteine, Q represents glutamine, E represents glutamic acid, and G represents glycine.
  • H represents histidine
  • I represents isoleucine
  • L represents leucine
  • K represents lysine
  • M represents methionine
  • F represents phenylalanine
  • P represents proline
  • S represents serine
  • T threonine
  • W tryptophan
  • Y tyrosine
  • V valine.
  • mesothelioma means a tumor derived from mesothelial cells.
  • Mesothelioma is known to include pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma, testicular mesothelioma, and the like, depending on the site of occurrence.
  • mesothelioma means benign mesothelioma and/or malignant mesothelioma.
  • Mesothelioma is roughly classified into epithelial mesothelioma, sarcomatous mesothelioma, biphasic mesothelioma, and other mesothelioma (such as desmoplastic type) according to histological type.
  • the mesothelioma can be malignant mesothelioma.
  • an antibody is an antibody that binds to HEG1 protein.
  • the HEG1 protein can be the HEG1 protein expressed in mesothelioma cells (eg ACC-MESO4 cell line) (WO2017/141604). HEG1 protein expressed in mesothelioma cells may have mesothelioma-specific glycosylation.
  • the sugar chain modification includes ⁇ 2,3-sialylation because it is decomposed by ⁇ 2,3-neuraminidase treatment (WO2017/141604).
  • the sugar chain modification can be O-type sugar chain modification because it is not degraded by N-glycanase (PNGase F) (WO2017/141604).
  • the antibodies of the present disclosure bind to HEG1 protein expressed on mesothelioma cells.
  • the antibody binds to the HEG1 protein in an O-glycosylation-dependent manner, including ⁇ 2,3 sialic acid. That is, antibodies can reduce or eliminate binding to HEG1 protein by ⁇ 2,3 neuraminidase treatment. Antibodies may also reduce or eliminate binding to HEG1 protein by proteinase K treatment.
  • humanized antibodies that bind to HEG1 (especially human HEG1) protein are provided.
  • the antibodies of the present disclosure bind HEG1 protein expressed on mesothelioma cells.
  • the antibody binds to the HEG1 protein in an O-glycosylation-dependent manner, including ⁇ 2,3 sialic acid. That is, antibodies can reduce or eliminate binding to HEG1 protein by ⁇ 2,3 neuraminidase treatment. Antibodies may also reduce or eliminate binding to HEG1 protein by proteinase K treatment.
  • the antibody of the present disclosure is an antibody that binds to HEG1 protein expressed in mesothelioma cells (eg, ACC-MESO4 cell line).
  • HEG1 protein expressed in mesothelioma cells eg, ACC-MESO4 cell line
  • Such antibodies can be obtained by conventional methods, eg, as described in WO2017/141604.
  • the antibody binds to HEG1 protein expressed in mesothelioma cells (e.g., ACC-MESO4 cell line), but in certain embodiments, the binding is abolished by proteinase K treatment of HEG1 protein. or can be lowered.
  • the antibody binds to HEG1 protein expressed on mesothelioma cells (eg, the ACC-MESO4 cell line), and in certain aspects, such binding can be abolished or reduced by ⁇ 2,3 neuraminidase treatment. . In some embodiments, the binding is not abolished by treatment with one or more or any selected from the group consisting of ⁇ -N-acetylglucosaminidase, N-glycanase (PNGaseF), lysozyme, and hyaluronidase. Processing is carried out under conditions suitable for the particular process. In some aspects, the antibody can be a human antibody.
  • Human antibodies can be generated by immunizing a non-human mammal (eg, mouse) that has integrated a human IgG locus with an immunogen.
  • a mouse in which a human heavy chain variable region has been inserted upstream of a mouse IgG heavy chain constant region and a human light chain variable region has been inserted upstream of a mouse IgG light chain constant region is immunized with an immunogen, and an antibody can also be obtained as a human chimeric antibody and constructed by replacing the constant regions with the corresponding human constant regions (see, eg, WO2002/066630A and WO2011/004192A).
  • Humanized antibodies can be made by removing six CDRs of a human antibody and replacing them with the corresponding CDRs (6 CDRs) of the resulting antibody.
  • the antibody or antigen-binding fragment thereof of the present disclosure is a humanized antibody that binds to a partial peptide of HEG1 (especially human HEG1) protein.
  • a partial peptide can be, for example, an antibody that binds to a peptide having the amino acid sequence set forth in SEQ ID NO: 182 (SKSPSLVSLPT).
  • the partial peptide can be, for example, a peptide produced by mesothelioma cells (eg, ACC-MESO4 cell line).
  • the peptide is fused to the N-terminal side of a protein (SEQ ID NO: 183; hereinafter referred to as “SLURPgpi”; the signal sequence is shown in SEQ ID NO: 184) in which a GPI anchor signal is connected to the N-terminus of human SLURP1. It can be obtained as a protein and used to evaluate the binding property to an antibody.
  • SEQ ID NO: 182 the peptide having the amino acid sequence set forth in SEQ ID NO: 182 (SKSPSLVSLPT) has glycosylation at either or both of Serine 1 and Serine 8.
  • the sugar chain modification can be 2,3-sialyl T antigen (2,3-Sialyl T) or disialyl T antigen (DiSialyl T).
  • the antibody is a peptide having the amino acid sequence set forth in SEQ ID NO: 182 (SKSPSLVSLPT), wherein either or both of Serine 1 and Serine 8 have glycosylation modifications.
  • SEQ ID NO: 182 SEQ ID NO: 182
  • an antibody is provided in which the sugar chain modification is 2,3-sialyl T antigen (2,3-Sialyl T) or disialyl T antigen (DiSialyl T).
  • the humanized antibody of the present disclosure has a heavy chain CDR1 having the amino acid sequence set forth in SEQ ID NO:37, a heavy chain CDR2 having the amino acid sequence set forth in SEQ ID NO:43, and an amino acid sequence set forth in SEQ ID NO:51
  • a heavy chain variable region comprising a heavy chain CDR3, a light chain CDR1 having the amino acid sequence set forth in SEQ ID NO:62, a light chain CDR2 having the amino acid sequence set forth in SEQ ID NO:75, and a light chain having the amino acid sequence set forth in SEQ ID NO:82. and a light chain variable region, including chain CDR3.
  • the humanized antibody of the present disclosure has a heavy chain CDR1 having the amino acid sequence set forth in SEQ ID NO:37, a heavy chain CDR2 having the amino acid sequence set forth in SEQ ID NO:43, and an amino acid sequence set forth in SEQ ID NO:51
  • a heavy chain variable region comprising a heavy chain CDR3, a light chain CDR1 having the amino acid sequence set forth in SEQ ID NO:63, a light chain CDR2 having the amino acid sequence set forth in SEQ ID NO:75, and a light chain having the amino acid sequence set forth in SEQ ID NO:82. and a light chain variable region, including chain CDR3.
  • the humanized antibody of the present disclosure has a set of heavy chain CDRs 1-3 of any of the following (1A)-(8A):
  • the humanized antibody of the present disclosure has a set of light chain CDRs 1-3 of any of the following (1B)-(18B): (1B) a light chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 116, a light chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 117, and a light chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 118; (2B) a light chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 119, a light chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 120, and a light chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 121; (3B) a light chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 122, a light chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 123, and a light chain CDR3 having the amino acid sequence set forth in SEQ ID NO: 124
  • the antibodies of the present disclosure are a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence set forth in SEQ ID NO:37, a heavy chain CDR2 having the amino acid sequence set forth in SEQ ID NO:43, and a heavy chain CDR3 having the amino acid sequence set forth in SEQ ID NO:51; It may comprise a light chain variable region comprising the set of light chain CDRs 1-3 of any of (1B)-(18B) above.
  • the antibodies of the present disclosure are A heavy chain variable region comprising the set of heavy chain CDRs 1 to 3 of any one of (1A) to (8A) above, a light chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 62, and having the amino acid sequence set forth in SEQ ID NO: 75
  • a light chain variable region comprising a light chain CDR2, a light chain CDR3 having the amino acid sequence set forth in SEQ ID NO:82.
  • the light chain CDR1 preferably has the amino acid sequence set forth in SEQ ID NO:63.
  • the antibodies of the present disclosure are A heavy chain variable region comprising a set of heavy chain CDRs 1-3 of any one of (1A) to (8A) above and a light chain variable region comprising a set of light chain CDRs 1-3 of any one of (1B) to (18B) above It can contain regions.
  • the antibodies of the present disclosure are a heavy chain variable region comprising the set of heavy chain CDRs 1-3 of (1A) above; It may comprise a light chain variable region comprising the set of light chain CDRs 1-3 of any of (1B)-(18B) above.
  • the light chain variable region may comprise the set of light chain CDRs 1-3 of (1B) above.
  • the light chain variable region may comprise the set of light chain CDRs 1-3 of any of (2B)-(18B) above.
  • the light chain variable region may comprise the set of light chain CDRs 1-3 of any of (2B)-(10B) above.
  • the light chain variable region may comprise the set of light chain CDRs 1-3 of any of (2B)-(7B) and (10B) above (especially (4B) or (10B)). In a preferred embodiment, the light chain variable region can be (10B) above.
  • the antibodies of the present disclosure are a heavy chain variable region comprising the set of heavy chain CDRs 1-3 of (2A) above; It may comprise a light chain variable region comprising the set of light chain CDRs 1-3 of any of (1B)-(18B) above.
  • the light chain variable region may comprise the set of light chain CDRs 1-3 of (1B) above.
  • the light chain variable region may comprise the set of light chain CDRs 1-3 of any of (2B)-(18B) above.
  • the light chain variable region may comprise the set of light chain CDRs 1-3 of any of (2B)-(10B) above.
  • the light chain variable region may comprise the set of light chain CDRs 1-3 of any of (2B)-(7B) and (10B) above (especially (4B) or (10B)). In a preferred embodiment, the light chain variable region can be (10B) above.
  • the antibodies of the present disclosure are a heavy chain variable region comprising the set of heavy chain CDRs 1-3 of (3A) above; It may comprise a light chain variable region comprising the set of light chain CDRs 1-3 of any of (1B)-(18B) above.
  • the light chain variable region may comprise the set of light chain CDRs 1-3 of (1B) above.
  • the light chain variable region may comprise the set of light chain CDRs 1-3 of any of (2B)-(18B) above.
  • the light chain variable region may comprise the set of light chain CDRs 1-3 of any of (2B)-(10B) above.
  • the light chain variable region may comprise the set of light chain CDRs 1-3 of any of (2B)-(7B) and (10B) above (especially (4B) or (10B)). In a preferred embodiment, the light chain variable region can be (10B) above.
  • the antibodies of the present disclosure are a heavy chain variable region comprising the set of heavy chain CDRs 1-3 of (4A) above; It may comprise a light chain variable region comprising the set of light chain CDRs 1-3 of any of (1B)-(18B) above.
  • the light chain variable region may comprise the set of light chain CDRs 1-3 of (1B) above.
  • the light chain variable region may comprise the set of light chain CDRs 1-3 of any of (2B)-(18B) above.
  • the light chain variable region may comprise the set of light chain CDRs 1-3 of any of (2B)-(10B) above.
  • the light chain variable region may comprise the set of light chain CDRs 1-3 of any of (2B)-(7B) and (10B) above (especially (4B) or (10B)). In a preferred embodiment, the light chain variable region can be (10B) above.
  • the antibodies of the present disclosure are A heavy chain variable region comprising the set of heavy chain CDRs 1-3 of (5A) above; It may comprise a light chain variable region comprising the set of light chain CDRs 1-3 of any of (1B)-(18B) above.
  • the light chain variable region may comprise the set of light chain CDRs 1-3 of (1B) above.
  • the light chain variable region may comprise the set of light chain CDRs 1-3 of any of (2B)-(18B) above.
  • the light chain variable region may comprise the set of light chain CDRs 1-3 of any of (2B)-(10B) above.
  • the light chain variable region is any of (2B) to (7B) and (10B) above (especially any of (4B), (7B), (10B), or (14B) to (16B) or) the set of light chain CDRs 1-3.
  • the light chain variable region can be (10B) above.
  • the antibodies of the present disclosure are a heavy chain variable region comprising the set of heavy chain CDRs 1-3 of (6A) above; It may comprise a light chain variable region comprising the set of light chain CDRs 1-3 of any of (1B)-(18B) above.
  • the light chain variable region may comprise the set of light chain CDRs 1-3 of (1B) above.
  • the light chain variable region may comprise the set of light chain CDRs 1-3 of any of (2B)-(18B) above.
  • the light chain variable region may comprise the set of light chain CDRs 1-3 of any of (2B)-(10B) above.
  • the light chain variable region is any of (2B) to (7B) and (10B) above (especially any of (4B), (7B), (10B), or (14B) to (16B) or) the set of light chain CDRs 1-3.
  • the light chain variable region can be (10B) above.
  • the antibodies of the present disclosure are a heavy chain variable region comprising the set of heavy chain CDRs 1-3 of (7A) above; It may comprise a light chain variable region comprising the set of light chain CDRs 1-3 of any of (1B)-(18B) above.
  • the light chain variable region may comprise the set of light chain CDRs 1-3 of (1B) above.
  • the light chain variable region may comprise the set of light chain CDRs 1-3 of any of (2B)-(18B) above.
  • the light chain variable region may comprise the set of light chain CDRs 1-3 of any of (2B)-(10B) above.
  • the light chain variable region may comprise the set of light chain CDRs 1-3 of any of (2B)-(7B) and (10B) above (especially (4B) or (10B)). In a preferred embodiment, the light chain variable region can be (10B) above.
  • the antibodies of the present disclosure are A heavy chain variable region comprising the set of heavy chain CDRs 1-3 of (8A) above; It may comprise a light chain variable region comprising the set of light chain CDRs 1-3 of any of (1B)-(18B) above.
  • the light chain variable region may comprise the set of light chain CDRs 1-3 of (1B) above.
  • the light chain variable region may comprise the set of light chain CDRs 1-3 of any of (2B)-(18B) above.
  • the light chain variable region may comprise the set of light chain CDRs 1-3 of any of (2B)-(10B) above.
  • the light chain variable region may comprise the set of light chain CDRs 1-3 of any of (2B)-(7B) and (10B) above (especially (4B) or (10B)). In a preferred embodiment, the light chain variable region can be (10B) above.
  • variable regions of the antibody onto which the heavy chain CDRs 1-3 and light chain CDRs 1-3 are grafted can be those of a human IgG1 antibody.
  • the antibody variable regions onto which the heavy chain CDRs 1-3 and light chain CDRs 1-3 are grafted can be human IgG2 antibody variable regions.
  • the antibody variable regions onto which the heavy chain CDRs 1-3 and light chain CDRs 1-3 are grafted can be human IgG3 antibody variable regions.
  • the antibody variable regions onto which the heavy chain CDRs 1-3 and light chain CDRs 1-3 are grafted can be human IgG4 antibody variable regions.
  • the Fc region in the antibodies of the present disclosure, can be the Fc region of a human IgG1 antibody. In certain preferred aspects, in the antibodies of the present disclosure, the Fc region (ie, heavy chain constant regions 2 and/or 3) can be the Fc region of a human IgG2 antibody. In certain preferred aspects, in the antibodies of the present disclosure, the Fc region (ie, heavy chain constant regions 2 and/or 3) can be the Fc region of a human IgG3 antibody. In certain preferred aspects, in the antibodies of the present disclosure, the Fc region (ie, heavy chain constant regions 2 and/or 3) can be the Fc region of a human IgG4 antibody.
  • the heavy chain variable region is framework region 1 having the amino acid sequence set forth in SEQ ID NO: 32; framework region 2 having the amino acid sequence set forth in SEQ ID NO: 40; framework region 3 having the amino acid sequence set forth in SEQ ID NO: 46; It may have a framework region 4 having the amino acid sequence set forth in 54.
  • the heavy chain variable region in the antibody of the present disclosure comprises framework region 1 having the amino acid sequence set forth in SEQ ID NO: 33, framework region 2 having the amino acid sequence set forth in SEQ ID NO: 40, and SEQ ID NO: It has framework region 3 having the amino acid sequence set forth in 46 and framework region 4 having the amino acid sequence set forth in SEQ ID NO:54.
  • SEQ ID NO: 46 X1 is A, X3 is T, X5 is E, X6 is R, X7 is T, and in SEQ ID NO: 54, X1 is V , X3 can be T, X4 can be Q or E, and X5 can be P.
  • the heavy chain variable region in the antibody of the present disclosure comprises framework region 1 having the amino acid sequence set forth in SEQ ID NO:33, framework region 2 having the amino acid sequence set forth in SEQ ID NO:42, and SEQ ID NO:48 and framework region 4 having the amino acid sequence set forth in SEQ ID NO:59.
  • the light chain variable region comprises framework region 1 having the amino acid sequence set forth in SEQ ID NO:57, framework region 2 having the amino acid sequence set forth in SEQ ID NO:72, and SEQ ID NO: 79 and framework region 4 having the amino acid sequence set forth in SEQ ID NO:86.
  • the light chain variable region comprises framework region 1 having the amino acid sequence set forth in SEQ ID NO:61, framework region 2 having the amino acid sequence set forth in SEQ ID NO:74, and SEQ ID NO: It may have framework region 3 having the amino acid sequence set forth in SEQ ID NO:81 and framework region 4 having the amino acid sequence set forth in SEQ ID NO:88.
  • the antibodies of the disclosure comprise one heavy chain variable region selected from the group consisting of SEQ ID NOs: 1-6, 8 and 9; and one light chain variable region selected from the group consisting of 29-31.
  • the antibodies of this disclosure have one heavy chain variable region selected from the group consisting of SEQ ID NOs:2, 4-6, 8, and 9; , and one light chain variable region selected from the group consisting of 29-31.
  • an antibody of the present disclosure may comprise a heavy chain variable region set forth in SEQ ID NO:6 and a light chain variable region set forth in SEQ ID NO:21.
  • Antibodies or antigen-binding fragments thereof of the present disclosure may include antibodies or antigen-binding fragments thereof having mutations selected from the group consisting of insertions, deletions, additions and substitutions of one to several amino acids.
  • an antibody or antigen-binding fragment thereof comprising at least three or more CDRs.
  • at least 2, 3, 4, 5, or 6 CDRs in or from an antibody or antigen-binding fragment thereof of the disclosure Antibodies with at least 2, 3, 4, 5, or 6 CDRs that are substantially identical to are included.
  • At least one, two, or three CDRs in an antibody or antigen-binding fragment thereof of the disclosure and at least about 85%, 86%, 87%, 88%, 89%, 90%, 95% %, 96%, 97%, 98%, or 99% identical at least 1, 2, 3, 4, 5, or 6 CDRs are included.
  • At least 1, 2, 3, 4, 5, or 6 CDRs are in or in an antibody or antigen-binding fragment thereof of the disclosure at least one insertion, deletion, addition or substitution in at least one, two, three, four, five, or six CDRs derived from An antibody or antigen-binding fragment thereof of the present disclosure has an amino acid sequence identity of 80% or more, 85% or more, 90% or more, or 95% or more and has the antigen specificity of an antibody or an antigen thereof A binding fragment may be included.
  • Antibodies or antigen-binding fragments thereof of the present disclosure include, for example, 80% or more, 85% or more, 90% or more, or 95% or more amino acid sequence identity in the framework regions with the antibodies disclosed above.
  • antibodies or antigen-binding fragments thereof of the present disclosure are selected from the group consisting of insertions, deletions, additions and substitutions of one to several amino acids in the antibodies disclosed above.
  • Antibodies or antigen-binding fragments thereof with mutations may be included.
  • the humanized IgG antibody can be an antibody that binds to a peptide having the amino acid sequence set forth in SEQ ID NO: 182 (SKSPSLVSLPT).
  • the partial peptide can be, for example, a peptide produced by mesothelioma cells (eg, ACC-MESO4 cell line).
  • a peptide can be obtained as a fusion protein by, for example, linking it to the N-terminal side of a protein in which a GPI anchor signal is linked to the N-terminus of human SLURP1, and used for evaluation of antibody binding.
  • the human antibody can be any of the human antibodies described above.
  • the humanized IgG antibody can be any of the above humanized antibodies.
  • an antibody of the present disclosure may comprise a heavy chain variable region set forth in SEQ ID NO:6 and a light chain variable region set forth in SEQ ID NO:21.
  • Non-limiting examples of heavy chain constant regions of IgG antibodies include heavy chain constant regions of IgGl, IgG2, IgG3, IgG4, and IgG4PE, with heavy chain constant regions of IgGl, IgG2, IgG4, IgG4PE being preferred; Heavy chain constant regions of IgG1 and IgG4PE are more preferred, and heavy chain constant regions of IgG4PE are even more preferred.
  • the IgG1 hinge region may have, for example, the amino acid sequence of SEQ ID NO:185.
  • the hinge region of IgG4 may have, for example, the amino acid sequence of SEQ ID NO:186, and the hinge region of IgG4PE may have, for example, the amino acid sequence of SEQ ID NO:187.
  • the CH2 region of IgG1 may have, for example, the amino acid sequence of SEQ ID NO:188.
  • the CH2 region of IgG4 and IgG4PE can have, for example, the amino acid sequence of SEQ ID NO:189.
  • Non-limiting examples of the light chain constant region of an IgG antibody include the light chain constant region of the ⁇ chain or the ⁇ chain, for example, the light chain constant region of the ⁇ chain.
  • the humanized antibodies of the present disclosure may or may not have internalizing activity for therapeutic and diagnostic purposes.
  • Method of treating mesothelioma in a subject comprises administering to the subject an effective amount of an antibody of the disclosure.
  • the subject can be a subject with mesothelioma.
  • the subject can be one diagnosed as having mesothelioma.
  • Administration can be performed by parenteral administration (eg, intraperitoneal administration, intrapleural administration, intratumoral administration, intravenous administration, etc.).
  • the dosage can be appropriately determined by a doctor, taking into consideration the subject's condition, body weight, sex and age. Administration can be single doses or multiple doses.
  • antibodies of the present disclosure are provided for use in the above methods.
  • the antibodies of the present disclosure can have antibody dependent cellular cytotoxicity (ADCC) activity and/or complement dependent cytotoxicity (CDC) activity.
  • ADCC activity means that when the antibody of the present invention binds to the cell surface antigen of target cells, Fc ⁇ receptor-bearing cells (effector cells) bind to the Fc portion via Fc ⁇ receptors and damage the target cells. means active.
  • ADCC activity can be determined by mixing HEG1-expressing target cells (eg, mesothelioma cells), effector cells, and the antibody of the present invention, and measuring the degree of ADCC.
  • target cells eg, mesothelioma cells
  • effector cells for example, mouse splenocytes, monocyte nuclei isolated from human peripheral blood or bone marrow can be used.
  • Mesothelioma cells expressing HEG1, for example, can be used as target cells.
  • Target cells are labeled with 51Cr or the like in advance, the antibody of the present invention is added thereto and incubated, and then effector cells at an appropriate ratio to the target cells are added and incubated. After incubation, the supernatant can be harvested and measured by counting the label in the supernatant.
  • CDC activity means cytotoxic activity by the complement system. CDC activity can be measured by using complement instead of effector cells in the ADCC activity test.
  • the antibodies of the present disclosure may themselves have anti-tumor effects.
  • Tumor growth inhibitory activity can be measured using tumor model animals. For example, a mouse is subcutaneously implanted with a tumor and administered with the antibody of the present invention. The tumor growth inhibitory effect can be measured by comparing the tumor tissue volume between the non-administered group and the administered group.
  • the tumor growth inhibitory activity of the present invention may be produced as a result of suppressing the growth of individual cells or as a result of inducing cell death.
  • the antibodies of the present disclosure may be linked to a cytotoxic agent (particularly a chemotherapeutic agent) via a linker. Therefore, according to the present disclosure, an antibody-drug conjugate comprising an antibody of the present disclosure and a cytotoxic agent, wherein the antibody and the cytotoxic agent are linked via a linker, can be provided.
  • Cytotoxic agents include chemotherapeutic agents (e.g., anticancer agents such as commercially available anticancer agents, e.g., auristatin (auristatin E, auristatin F phenylenediamine (AFP), monomethylauristatin E, monomethyloli statins F and their derivatives), maytansinoids DM1 and DM4 and their derivatives), camptothecins (SN-38, irinotecan, roottecan, DB67, BMP1350, ST1481, CKD602, topotecan and exatecan, and their derivatives), DNA Groove binders (enediyne, lexitropsin, duocarmycin and their derivatives), taxanes (paclitaxel and docetaxel and their derivatives), polyketides (discodermolide and its derivatives), anthraquinones (mitoxantrone and its derivatives) , benzodiazepines (pyrrolobenzodiazepines, ind
  • a non-cleavable linker or a cleavable linker (including, for example, valine-citrulline dipeptide) can be used as the linker.
  • compositions are provided that include the antibodies of the present disclosure. According to this disclosure, pharmaceutical compositions comprising the antibodies of this disclosure are disclosed. Pharmaceutical compositions of the present disclosure can be used to treat mesothelioma. The disclosure also provides compositions comprising the antibody-drug conjugates of the disclosure. According to the present disclosure, pharmaceutical compositions comprising the antibody-drug conjugates of this disclosure are disclosed. Pharmaceutical compositions of the present disclosure can be used to treat mesothelioma.
  • the pharmaceutical composition of the present disclosure may further contain pharmaceutically acceptable carriers, excipients, and/or additives.
  • carriers and additives include water, saline, phosphate buffer, dextrose, glycerol, pharmaceutically acceptable organic solvents such as ethanol, collagen, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, sodium carboxymethylcellulose, Sodium polyacrylate, sodium alginate, water-soluble dextran, sodium carboxymethyl starch, pectin, methylcellulose, ethylcellulose, xanthan gum, gum arabic, casein, agar, polyethylene glycol, diglycerin, glycerin, propylene glycol, petrolatum, paraffin, stearyl alcohol , stearic acid, human serum albumin, mannitol, sorbitol, lactose, surfactants, and the like.
  • compositions of the present invention can be in various forms, such as liquid formulations (eg, injections).
  • Preferred embodiments are injections or infusion preparations, which are preferably administered parenterally (eg, intravenously, transdermally, subcutaneously, intradermally, intraperitoneally, intrapleurally, intramuscularly, intratumorally).
  • a humanized antibody is prepared according to a conventional method so as to have amino acid sequences of various variable regions to which signal sequences derived from mouse antibodies are added, and amino acid sequences of constant regions of human IgG1. Designed.
  • the nucleotide sequence encoding the designed humanized antibody was deliberately altered for codon usage suitable for expression in Chinese Hamster Ovary (CHO) cells.
  • a Kozak sequence was added to the nucleotide sequence obtained by conversion and the initiation codon site of the signal sequence.
  • a mammalian cell expression plasmid (pcDNA3.1) having a stop codon added to the C-terminal side of the constant region and restriction enzyme sites added upstream of the Kozak sequence and downstream of the stop codon was treated with restriction enzymes and ligated. The resulting sequence was incorporated into a plasmid.
  • Each H chain expression plasmid and each L chain expression plasmid obtained are combined into one type of H chain and one type of L chain, and expressed in ExpiCHO Expression System (ThermoFisher Scientific) or RK13 cells. , was collected from the culture supernatant with HiTrap protein G (1 mL) (Cytiva), eluted with 0.1 M glycine buffer (pH 2.8), and dialyzed against PBS for purification.
  • Humanized antibodies were obtained by the method described above. Antibody activity of each obtained antibody was measured by ELISA using 7.62EGF as an antigen.
  • 7.62EGF is a secretory protein in which an antibody epitope region is linked to the N-terminal side of the EGF domain region of HEG1, and a His tag is linked to the C-terminal side. be done.
  • 7.62EGF purified from the culture supernatant of constitutively expressing cells was adsorbed to an ELISA plate and blocked with 1% BSA. The culture supernatant of RK13 cells transfected with the humanized antibody gene was added to the plate and allowed to react at room temperature for 3 hours.
  • Biacore used a His-tagged synthetic glycopeptide as a ligand and an antibody as an analyte.
  • a sensor chip NTA to which Ni2+ was bound was used as the sensor chip.
  • Affinity was calculated according to the Biacore X100 protocol.
  • Flow cytometry was performed using purified antibody at 10 ⁇ g/mL as the primary antibody and FITC-goat anti-human IgG F(ab)'2 at 25 ⁇ g/mL as the secondary antibody. The black line is without primary antibody (negative control), and the red line is with each primary antibody added. Neither Biacore nor flow cytometry showed significant differences between each antibody.

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WO2024181576A1 (ja) 2023-03-02 2024-09-06 日本メジフィジックス株式会社 放射性金属標識抗体、放射性医薬、及び化合物
EP4674439A1 (en) 2023-03-02 2026-01-07 Nihon Medi-Physics Co., Ltd. Radioactive metal labeled antibody, radiopharmaceutical, and compound

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