WO2020114479A1 - Molécule de protéine multispécifique - Google Patents

Molécule de protéine multispécifique Download PDF

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WO2020114479A1
WO2020114479A1 PCT/CN2019/123555 CN2019123555W WO2020114479A1 WO 2020114479 A1 WO2020114479 A1 WO 2020114479A1 CN 2019123555 W CN2019123555 W CN 2019123555W WO 2020114479 A1 WO2020114479 A1 WO 2020114479A1
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seq
antibody
region
polypeptide chain
antigen
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PCT/CN2019/123555
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Chinese (zh)
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应华
张玲
杨筱莹
葛虎
陶维康
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Priority to CN201980072293.5A priority Critical patent/CN112969476A/zh
Publication of WO2020114479A1 publication Critical patent/WO2020114479A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells

Definitions

  • B7H3 expression is positively correlated with clinical pathological malignancy (such as tumor volume, extraprostatic invasion, or Gleason score), and also with cancer progression (Cancer Res. 2007 Aug 15; 67 (16):7893-7900).
  • clinical pathological malignancy such as tumor volume, extraprostatic invasion, or Gleason score
  • cancer progression Cancer Res. 2007 Aug 15; 67 (16):7893-7900.
  • B7H3 expression is negatively correlated with event-free survival
  • pancreatic cancer B7H3 expression is correlated with lymph node metastasis and pathological progression. Therefore, B7H3 is considered to be a new tumor marker and a potential therapeutic target.
  • CD3 antibody molecules such as OKT3, UCHT-1, SP34 (Silvana Pessano et al. The EMBO Journal. 1985, 4(2): 337-344), and at the same time, such as CN103703024, WO2017055389, CN102171248, etc.
  • Some CD3 antibody molecules are also disclosed. However, in the development of drugs, it is still necessary to develop more safe and effective CD3 antibody molecules.
  • the first polypeptide chain of the multispecific protein molecule has the structure of formula I as follows:
  • HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 37, 40 and 43 respectively;
  • the antigen-binding region for CD3 in the multispecific protein molecule comprises a light chain variable region as shown in SEQ ID NO: 36 and/or is selected from SEQ ID NO: 29, 30, The heavy chain variable region shown in any one of 31, 32, and 35.
  • the antigen-binding region for B7H3 in the multispecific protein molecule comprises scFv as shown in SEQ ID NO: 51, 52, 53 or 54.
  • amino acid sequence of the first polypeptide chain is shown in SEQ ID NO: 77;
  • the present disclosure relates to a recombinant vector comprising the isolated nucleic acid molecule as described above.
  • the present disclosure relates to a multispecific protein molecule as described above or a pharmaceutical composition as described above or an isolated nucleic acid molecule as described above as a drug, preferably the drug is an activated T cell
  • the drug is more preferably a drug for treating cancer or a drug for treating autoimmune or inflammatory diseases.
  • the present disclosure relates to a method of treating cancer or an autoimmune or inflammatory disease, the method comprising administering to a subject a therapeutically effective amount of a multispecific protein molecule as described above or as previously described
  • the pharmaceutical composition described above, or the isolated nucleic acid molecule as described above Preferably, the method comprises administering to the subject a unit-containing composition containing 0.1-3000 mg of the multispecific protein molecule as described above, or the pharmaceutical composition as described above, or as previously described Isolated nucleic acid molecule.
  • the cancer is a B7-H3 positive cell-associated cancer; preferably breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, kidney cancer, lung cancer, liver cancer, gastric cancer, colon cancer, bladder cancer, Esophageal cancer, cervical cancer, gallbladder cancer, glioblastoma and melanoma.
  • Figure 4A to Figure 4B Comparison of the killing activity of B7H3 single and bivalent bispecific antibodies containing the same CD3 scFv against A498.
  • Figure 4A is a comparison of the killing activity of B7H3 containing HRH1 monovalent (181) and bivalent (131) bispecific antibodies.
  • Fig. 4B is a comparison of the killing activity of the monovalent (187) and divalent (177) B7H3 containing HRH7.
  • the experimental results all show that B7H3 bivalent bispecific antibody has a significant A498 killing activity than B7H3 monovalent bispecific antibody, and meanwhile, B7H3 bivalent bispecific antibody has significantly enhanced killing activity than B7H3 monovalent bispecific antibody.
  • Fig. 5A to Fig. 5C The killing activity of B7H3 bivalent bispecific antibody containing the same CD3 heavy chain variable region and different structural sequences on A498.
  • Fig. 5A is a comparison of the killing activity between the bivalent bispecific antibodies of B7H3 (AFF1, AFF2, AFF3, AFF4) in which the order of the first polypeptide chain containing HRH2 is different.
  • Fig. 5B is a comparison of the killing activity between (AFF3, AFF3-B) B7H3 bivalent bispecific antibodies with different order of the second polypeptide chain containing HRH2.
  • Figures 6A-6B Detection of activation of Jurkat recombinant cells by different antibodies.
  • Fig. 6A is antibody-mediated activation of B7H3 target-specific Jurkat recombinant cells in the case of A498 cells;
  • Fig. 6B is antibody-mediated non-B7H3 target-specific Jurkat recombination without A498 cells Cell activation.
  • the antibodies indicated in the legends in Figure 6A and Figure 6B are identical.
  • FIG. 7A to 7B Detection of activation of Jurkat recombinant cells with different valence bispecific antibodies containing the same CD3scFv.
  • Figure 7A is the B7H3 mono/bivalent bispecific antibody in the case of A498 cells, antibody-mediated B7H3 target specific Jurkat recombinant cell activation;
  • Figure 7B is the B7H3 mono/bivalent bispecific antibody without A498 In the case of cells, mediated activation of Jurkat recombinant cells specific for non-B7H3 targets.
  • Each light chain includes a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region.
  • the light chain constant region contains one region (domain, CL1).
  • the VH and VL regions can be further subdivided into hypervariable regions, called complementarity determining regions (CDRs), with more conservative regions interspersed between them, called framework regions (FR, also called framework regions, framework regions).
  • CDRs complementarity determining regions
  • FR also called framework regions, framework regions.
  • Each VH and VL is composed of three CDRs and four FRs, arranged from the amino end to the carboxy end in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • This DNA is known and/or can be easily obtained from, for example, commercially available sources, DNA databases (including, for example, phage-antibody databases) or can be synthesized.
  • This DNA can be sequenced and manipulated chemically or through the use of molecular biotechnology, such as arranging one or more variable and/or constant regions into a suitable configuration, or introducing codons to generate cysteine residues, modifications , Add or delete amino acids, etc.
  • a “chimeric antibody” is an antibody obtained by fusing the variable region of a murine antibody and the constant region of a human antibody, which can reduce the immune response induced by the murine antibody.
  • To build a chimeric antibody first build a hybridoma that secretes murine specific monoclonal antibodies, then clone the variable region gene from the mouse hybridoma cells, and then clone the human antibody constant region gene as needed.
  • the chimeric gene is linked to the human constant region gene and inserted into an expression vector, and finally the chimeric antibody molecule is expressed in a eukaryotic system or a prokaryotic system.
  • Linker or "linker” or “linker” or “L1” used to connect two protein domains refers to the connecting polypeptide sequence used to connect protein domains, usually has a certain flexibility, the use of linker will not The original function of the protein domain is lost.
  • VH TAA and VL TAA represent epitopes of antibody variable regions that bind to tumor-associated antigens
  • VH CD3 and VL CD3 represent The variable region of the antibody binds to the epitope of CD3.
  • tumor antigen refers to a substance produced by tumor cells, optionally a protein, including “tumor-associated antigen” or “TAA” (which means produced in tumor cells and compared to corresponding normal tissues in cancer Differentially expressed proteins) and “tumor specific antigen” or “TSA” (which refers to tumor antigens produced in tumor cells and specifically expressed or abnormally expressed in cancer compared to corresponding normal tissues).
  • TAA tumor-associated antigen
  • TSA tumor specific antigen
  • Epitope or “antigenic determinant” refers to a site on an antigen where immunoglobulins or antibodies specifically bind. Epitopes typically include at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive or non-contiguous amino acids in a unique spatial conformation. See, for example, Epitope Mapping Protocols Methods Molecular Biology, Volume 66, G.E. Morris, Ed. (1996).
  • antibodies bind with an affinity (KD) of about less than 10 -8 M, such as about less than 10 -9 M, 10 -10 M, 10 -11 M or less.
  • affinity refers to the strength of the interaction between antibody and antigen at a single epitope. Within each antigenic site, the variable region of the "arm" of the antibody interacts with the antigen at multiple amino acid sites through weak non-covalent forces; the greater the interaction, the stronger the affinity.
  • an antibody or antigen-binding fragment thereof e.g. Fab fragments
  • the term “high affinity” generally refers to having a K D 1E -9 M in K D or less (e.g.
  • the two sequences are 60% homologous; if there are 95 matches at 100 positions in the two sequences Or homology, then the two sequences are 95% homologous.
  • a comparison is made when aligning two sequences to give the largest percentage homology.
  • the comparison can be performed by the BLAST algorithm, where the parameters of the algorithm are selected to give the maximum match between the individual sequences over the entire length of the individual reference sequences.
  • Inflammatory disorder refers to any disease, disorder or syndrome in which an excessive or unregulated inflammatory response results in excessive inflammatory symptoms, damage to the host tissue, or loss of tissue function.
  • Inflammatory disease also refers to a pathological condition mediated by the aggregation of leukocytes or neutrophil chemotaxis.
  • Inflammation refers to a local protective response caused by tissue damage or destruction, which is used to destroy, weaken, or prevent (isolate) harmful substances and injured tissues. Inflammation is significantly associated with the aggregation of leukocyte or neutrophil chemotaxis. Inflammation can be caused by pathogenic objects and viruses and non-infectious causes such as reperfusion or stroke after trauma or myocardial infarction, immune responses to foreign antigens, and autoimmune responses.
  • a natural single-chain phage antibody library was constructed. After packaging the constructed natural single-chain phage antibody library to form phage particles, the liquid phase method was used for panning, the phage was combined with the biotinylated B7H3 liquid phase, and then separated by streptavidin magnetic beads. In order to obtain a positive sequence that binds to human B7H3, biotinylated human B7H3 was used for panning, and several monoclonal colonies were picked and packaged as phage single-chain antibodies for phage ELISA testing. The binding activity of monoclonal phage to human B7H3 and mouse B7H3 was tested respectively, and B7H3 antibody was obtained after screening.
  • the cross-lined part is the extracellular region of B7H3; the italic part is the His tag.
  • the dash-dotted line is the transmembrane area (Transmembrane domain:467-487);
  • the h1702 sequence of the B7H3 antibody and the CDR sequence defined by the IMGT numbering rules are as follows:
  • cysteine substitution mutations were performed in the VH and VL of the B7H3 antibody h1702, respectively, and G103C (natural sequence number of amino acids was introduced in the light chain variable region, in SEQ ID NO: 16 Position 103) mutation, introducing a G44C (natural amino acid numbering in SEQ ID NO: 15 position 44) mutation in the heavy chain variable region to form a pair of disulfide bonds, the mutated anti-B7H3 single chain antibody
  • G103C natural sequence number of amino acids was introduced in the light chain variable region, in SEQ ID NO: 16 Position 103 mutation, introducing a G44C (natural amino acid numbering in SEQ ID NO: 15 position 44) mutation in the heavy chain variable region to form a pair of disulfide bonds, the mutated anti-B7H3 single chain antibody
  • the cross-lined part is CD3 ⁇ extracellular domain (Extracellular Domain: 22-108); the italic part is His-tagged mouse CD3 ⁇
  • the double horizontal line is the signal peptide (Signal peptide: 1-22);
  • the cross-lined part is the CD3 ⁇ extracellular domain (Extracellular domain: 23-126), of which 32-112 is Ig-like Domain;
  • the double horizontal line is the signal peptide (Signal peptide: 1–21);
  • the dashed-dotted line is the transmembrane area (Transmembrane domain: 106-126);
  • the cross-lined part is the CD3 ⁇ extracellular domain (Extracellular domain: 22-105);
  • the italic part is the intracellular domain (Cytoplasmic domain: 127-171).
  • the sequence of the light chain variable region is as follows:
  • the light and heavy chain variable regions derived from the above B7H3 antibody and the light and heavy chain variable regions derived from the CD3 antibody can be connected to form scFv for B7H3 and scFv for CD3 respectively, wherein the linker can be selected from well known in the art
  • the exemplary linker may be selected from: (GGGGS)n or (GGGGS)nGGG, where n may be 1, 2, 3 or 4.
  • the structure of the B7H3 bivalent bispecific antibody is shown in FIG. 1A.
  • the C-terminal may or may not be connected to the His tag.
  • the asymmetric structure design of two chains containing Fc has two B7H3 antigen binding domains and one CD3 antigen binding domain.
  • the B7H3 antigen binding domains are one on each of the two chains, and the antigen binding domains are in the form of scFv.
  • the Fc region can maintain the normal half-life and good stability of the antibody.
  • the design of the two chains greatly reduces the probability of mismatches and improves the uniformity of the sample and the yield of the target antibody.
  • the molecular structure (Format) of the specific bispecific antibody is shown in Table 6 below.
  • the molecular structure of the B7H3 monovalent bispecific antibody used in some embodiments of the present disclosure has only the Fc domain in the second polypeptide chain, not Contains the antigen-binding domain, the structure is shown in Figure 1B.
  • the order is VL B7H3- linker-VH B7H3- linker-Fc.
  • the underlined part of the sequence is the B7H3 antibody sequence, and the italic part is the hole-Fc sequence.
  • Bispecific antibody CD3VH included BIAcore KD(M) 131 HRH-1 4.07E-08 113 HRH-2 7.72E-08
  • Exemplary selection of antibodies comprising HRH3 as the heavy chain variable region of the CD3 antigen binding domain is tested, wherein the affinity of the test antibodies 118, 127, and 132 for human (human) B7H3 and human CD3 is 10 -9 and 10 ⁇ , respectively
  • the 8 M level is comparable to the affinity of MGD009, and has strong cross-binding activity with cyno B7H3 and human CD3.
  • bivalent bispecific antibodies 118, 127, and 132 of B7H3 and the negative control antibody NC2 (retaining the B7H3 binding domain, only the CD3 binding domain was replaced with unrelated antibodies) were able to bind to the A498 cell line that highly expressed B7H3 ( (See Figure 2A). It has a gradient-dependent effect, is stronger than MGD009, and is specific for the B7H3 target.
  • the negative control antibody NC1 (the B7H3 binding domain is replaced with an unrelated antibody but retains the CD3 binding domain) does not bind to A498.
  • bispecific antibodies 118, 127 and 132, MGD009 and NC2 strongly bind to CT26/hB7H3 (see Figure 2B), but not to the CT26 cell line that does not express B7H3 (see Figure 2C), which also fully illustrates the test
  • the bispecific antibody specifically binds to the B7H3 target on the cell membrane surface.
  • Bispecific antibody-mediated killing experiments of PBMC on tumor cells were achieved by quantitatively detecting cell proliferation.
  • Use Cell Titer-glo to detect the content of ATP in cells, and ATP is an indicator of the metabolism of living cells, which is directly proportional to the number of cells in culture.
  • Inhibition rate% 100% - ( sample signal value - Blank signal value) / (control signal value - blank value signal)
  • Non-tumor cell specific Jurkat recombinant cells are activated by directly adding Jurkat recombinant cells and the antibody to be tested to a blank 96-well culture plate. After the co-cultivation, add 100 ⁇ l of Bright-Glo Reagent (Bright-Glo TM Luciferase Assay System, Promega, Cat#: E2620) to each well, place at room temperature for 5-10 min, and read the chemiluminescence using a multi-functional microplate reader
  • Bright-Glo Reagent Bright-Glo TM Luciferase Assay System, Promega, Cat#: E2620
  • B7H3 bivalent bispecific antibodies 118, 127 and 132 were used to detect the activation of Jurkat recombinant cells in the presence or absence of A498 to verify the specific and non-specific activation effects of bispecific antibodies on T cells.
  • the results showed that the B7H3 bivalent bispecific antibodies 118, 127 and 132 in different arrangements in the presence of the tumor cell line A498 (see Figure 6A) can effectively activate the Jurkat recombinant cell line and significantly induce luciferase Expression, because the negative control antibody NC1 cannot induce luciferase expression, can prove that the activation of Jurkat recombinant cells is specific to the B7H3 target.
  • the effector cells redirect the target cells under the guidance of bispecific antibodies, and release cytokines while killing the target cells.
  • the cytokine secretion is the quantitative detection of cytokine content in the cell culture supernatant by ELISA method, including IL2, IFN ⁇ , TNF ⁇ .
  • ELISA steps please refer to the instructions in the kit (Human IL-2 ELISA kit, Human IFN- ⁇ ELISA Kit, Human TNF- ⁇ ELISA kit, Xinbosheng, Cat#EHC003.96, EHC102g.96, EHC103a.96).
  • Test Example 6 Pharmacodynamic experiment of mouse 498 model reconstructed by human PBMC
  • This test example uses the A498 model (ATCC) of NOG mice (Beijing Viton Lihua Laboratory Animal Co., Ltd.) reconstructed by human PBMC to evaluate the anti-tumor efficacy of the CD3-B7H3 bispecific antibody of the present invention tested in mice.
  • mice Inoculate 5 ⁇ 10 6 cells/mouse/100 ⁇ l (containing 50% matrigel) of A498 cells under the skin of the right rib of NOG mice.
  • the mice are randomly grouped. 5-6 animals per group, and the day of grouping was defined as the day 0 of the experiment.
  • day 0 or day 1 freshly extracted PBMCs of 2 volunteers were mixed in a 1:1 ratio, injected into the abdominal cavity of NOG mice at 5 ⁇ 10 6 cells/100 ⁇ l, and each antibody was started intraperitoneally. 2 times a week, a total of 6 doses, 2 times a week to monitor tumor volume, animal weight and record data.
  • Vehicle is a negative control group in which PBS buffer is used instead of antibody administration.
  • the anti-tumor rate of antibody 126 reached 47.78% (p ⁇ 0.01) on the 21st day.
  • Antibody 127mpk the tumor suppression rate reached 76.20% (p ⁇ 0.001) on the 12th day, and the tumor suppression effect continued to increase by the 21st day, the tumor suppression rate was greater than 100% (p ⁇ 0.001), 3 out of 5 animals Compared with the grouping, the tumor volume had contracted, and the other two tumors completely regressed.
  • Antibody 132 had a tendency to inhibit tumor growth at a dose of 3.6 mpk (Figure 11B), and the tumor suppression rate reached 26.35% on the 13th day.
  • the half-life of antibodies 118, 127 and 132 in the B7H3 antigen binding region was 4.9-8.1 days, slightly longer than MGD009, reaching the level of ordinary IgG antibodies, and the half-life of CD3 antigen binding region was 3.2-5.6 days.
  • the kinetic parameters of antibody 118 in two different antigen binding regions of B7H3 and CD3 are not much different, indicating that the integrity of the molecule in vivo is good, and the half-lives are 4.9 and 4.4 days, respectively.
  • the half-life of antibody 127 in two different antigen-binding regions of B7H3 and CD3 is 4.9 and 3.2 days, respectively. The difference in exposure and clearance rate is more obvious.
  • the CD3 part is worse.
  • Antibody 132 is based on the molecular sequence of antibody 127, and a pair of disulfide bonds are added inside B7H3scFv. This modification greatly improves the half-life of the molecule (65-75%), and also has a greater improvement in exposure and clearance rate. .

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Abstract

L'invention concerne une molécule de protéine multispécifique. L'invention concerne plus particulièrement une molécule de protéine multispécifique ayant une nouvelle forme développée. Un anticorps multispécifique peut être lié simultanément à CD3 et à d'autres antigènes associés à une tumeur, et est lié à un lymphocyte T positif à CD3, et active celui-ci, tout en étant lié à une cellule d'expression d'antigène associée à une tumeur, et favorisant ainsi la mort du lymphocyte T sur la spécificité de cellule tumorale exprimant l'antigène associé à une tumeur. La présente invention concerne également la préparation et l'application d'un anticorps multispécifique.
PCT/CN2019/123555 2018-12-07 2019-12-06 Molécule de protéine multispécifique WO2020114479A1 (fr)

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WO2023284806A1 (fr) * 2021-07-14 2023-01-19 江苏恒瑞医药股份有限公司 Molécule de liaison à l'antigène qui se lie spécifiquement à cd38, bcma et cd3 et ses utilisations médicales
WO2023029089A1 (fr) * 2021-09-03 2023-03-09 苏州近岸蛋白质科技股份有限公司 Anticorps humanisé anti-cd3
WO2023088295A1 (fr) * 2021-11-17 2023-05-25 江苏先声药业有限公司 Anticorps multi-spécifique et utilisation pharmaceutique associée

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WO2024037626A1 (fr) * 2022-08-19 2024-02-22 盛禾(中国)生物制药有限公司 Anticorps bispécifique se liant à tnfr2 et à 4-1bb

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