WO2023143590A1 - Polythérapie antitumorale utilisant un anticorps anti-il-11 - Google Patents

Polythérapie antitumorale utilisant un anticorps anti-il-11 Download PDF

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WO2023143590A1
WO2023143590A1 PCT/CN2023/073746 CN2023073746W WO2023143590A1 WO 2023143590 A1 WO2023143590 A1 WO 2023143590A1 CN 2023073746 W CN2023073746 W CN 2023073746W WO 2023143590 A1 WO2023143590 A1 WO 2023143590A1
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amino acid
antibody
seq
acid sequence
tumor
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PCT/CN2023/073746
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Chinese (zh)
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王双
曾大地
张畅
王荣娟
焦莎莎
张锦超
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迈威(上海)生物科技股份有限公司
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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
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • 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
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244—Interleukins [IL]

Definitions

  • the invention relates to the field of biopharmaceuticals, in particular, the invention relates to a tumor combination therapy using an anti-interleukin-11 (Interleukin-11, IL-11) antibody.
  • Interleukin-11 Interleukin-11, IL-11
  • immunotherapy has achieved excellent therapeutic effects in various tumors or cancers such as melanoma and non-small cell lung cancer, especially for programmed death-1 (PD-1), programmed death ligand 1 (PD-L1 ) antibodies are considered the latest breakthrough in cancer immunotherapy.
  • PD-1 programmed death-1
  • PD-L1 programmed death ligand 1
  • Early preclinical evidence showed that the activation of PD-1 and PD-L1 inhibited the activation and proliferation of tumor antigen-specific T cells, promoted tumorigenesis, and negatively regulated T cell immune function; blocking this interaction Activates the immune system to fight cancer.
  • combination therapies In view of the clinical limitations of monotherapy with IO drugs, more and more combination therapies have emerged.
  • the guiding principle for most combination therapies is to improve tumor antigen presentation or rescue dysfunctional Immune effector cells to enhance the efficacy of target blockade.
  • the combined use of different cancer therapies can improve response rates.
  • anti-interleukin-11 (IL-11) antibodies can effectively enhance the efficacy of anti-tumor drugs, such as immune checkpoint agonists or inhibitors.
  • the object of the present invention is to provide a combination therapy of an antibody targeting IL-11 or a fragment thereof and other antitumor drugs for treating tumors.
  • treating refers to one or more of the following: delaying or inhibiting tumor growth, reducing tumor cell load or tumor burden, promoting tumor regression, causing tumor shrinkage, necrosis and/or Or disappear, prevent tumor recurrence, prolong the survival duration of the individual, etc.
  • antibody used in the present invention covers any known antibody form capable of specifically binding or targeting an antigen or target, including naturally occurring, artificially obtained or artificially constructed functional antibody proteins.
  • antibody fragment encompasses various functional or active fragments of antibodies, such as antigen-binding fragments thereof.
  • the present invention provides a pharmaceutical combination comprising:
  • the anti-tumor drugs can cause local upregulation of IL-11 expression and/or activation of signaling pathways by killing tumor cells in the tumor microenvironment.
  • the anti-IL-11 antibody or its fragment can block or inhibit the activation of IL-11 downstream signaling pathway by binding to IL-11.
  • the anti-IL-11 antibody or fragment thereof is capable of binding the antigen IL-11, especially human IL-11, with high affinity.
  • the present invention provides the following antibodies: a murine antibody obtained by using human IL-11 or murine IL-11 as an immunogen, and a human-derived antibody obtained by humanizing the murine antibody Humanized antibodies, and antibodies obtained by optimizing the sequence of the humanized antibodies using yeast display technology.
  • the anti-IL-11 antibody or its fragment can block or inhibit the activation of IL-11 downstream signaling pathway by binding to IL-11.
  • anti-IL-11 antibodies or fragments thereof provided by the present invention include:
  • Heavy chain variable region which includes complementarity determining regions (CDRs) 1 (H-CDR1), 2 (H-CDR2) and 3 (H-CDR3); and, the light chain variable region (VL), which includes CDRs 1 (L-CDR1), 2 (L -CDR2) and 3 (L-CDR3).
  • the anti-IL-11 antibody or fragment thereof in the anti-IL-11 antibody or fragment thereof:
  • the heavy chain variable region comprises heavy chain CDR1 (H-CDR1), heavy chain CDR2 (H-CDR2) and heavy chain CDR3 (H-CDR3) derived from the heavy chain variable region shown in the following amino acid sequence ):
  • the light chain variable region comprises light chain CDR1 (L-CDR1), light chain CDR2 (L-CDR2) and light chain CDR3 (L-CDR3) derived from the light chain variable region shown in the following amino acid sequence:
  • the heavy chain variable region comprises heavy chain CDR1 (H-CDR1), heavy chain CDR2 (H-CDR2) and heavy chain CDR3 (H-CDR3) derived from the heavy chain variable region shown in the following amino acid sequence ):
  • the light chain variable region comprises light chain CDR1 (L-CDR1), light chain CDR2 (L-CDR2) and light chain CDR3 (L-CDR3) derived from the light chain variable region shown in the following amino acid sequence:
  • Each amino acid sequence in the above group (1) and group (2) is the amino acid sequence of the heavy chain variable region or the light chain variable region of the anti-IL-11 antibody provided in the present invention, respectively.
  • definition tools such as Chothia, Kabat, IMGT, Contact, etc.
  • Kabat tool can be used to divide CDRs in the variable region sequence.
  • the heavy chain variable region and the light chain variable region respectively comprise the heavy chain variable region and the light chain shown in the following amino acid sequence pairing Heavy chain CDR1, heavy chain CDR2 and heavy chain CDR3 and light chain CDR1, light chain CDR2 and light chain CDR3 of the variable region:
  • the Kabat tool can be used to divide the CDRs in each variable region sequence in the above amino acid sequence pairing; in the case of the above pairing, the combination of CDRs of the heavy chain variable region and the light chain variable region is contained in In the anti-IL-11 antibody or fragment thereof provided by the present invention.
  • the heavy chain variable region and the light chain variable region comprise a combination of heavy chain CDRs and light chain CDRs selected from the following (H-CDR1 , H-CDR2, H-CDR3; and, L-CDR1, L-CDR2, L-CDR3):
  • H-CDR1, H-CDR2, and H-CDR3 comprising the amino acid sequences shown in SEQ ID NO.29, SEQ ID NO.30, and SEQ ID NO.31 in sequence; and, comprising sequentially shown in SEQ ID L-CDR1, L-CDR2, L-CDR3 of the amino acid sequences of NO.32, SEQ ID NO.33, and SEQ ID NO.34;
  • H-CDR1, H-CDR2, and H-CDR3 comprising the amino acid sequences shown in SEQ ID NO.29, SEQ ID NO.35, and SEQ ID NO.31 in turn; and, comprising sequentially shown in SEQ ID L-CDR1, L-CDR2, L-CDR3 of the amino acid sequences of NO.36, SEQ ID NO.33, and SEQ ID NO.34;
  • H-CDR1, H-CDR2, and H-CDR3 comprising the amino acid sequences shown in SEQ ID NO.23, SEQ ID NO.24, and SEQ ID NO.25 in sequence; and, comprising sequences shown in SEQ ID L-CDR1, L-CDR2, L-CDR3 of the amino acid sequences of NO.26, SEQ ID NO.27, SEQ ID NO.28; or
  • H-CDR1, H-CDR2, and H-CDR3 comprising the amino acid sequences shown in SEQ ID NO.37, SEQ ID NO.38, and SEQ ID NO.25 in sequence; and, comprising sequences shown in SEQ ID L-CDR1, L-CDR2, and L-CDR3 of the amino acid sequences of NO.39, SEQ ID NO.27, and SEQ ID NO.28.
  • the antibody or fragment thereof provided by the present invention is an anti-human interleukin-11 (hIL-11) antibody or fragment thereof.
  • hIL-11 anti-human interleukin-11
  • GenBank GenBank: AAH12506.1.
  • the anti-IL-11 antibody or fragment thereof provided by the present invention at least comprises a heavy chain variable region and
  • the light chain variable regions both include the above CDRs and the framework region (framework region, FR) therebetween, and the arrangement of each region is FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4.
  • the heavy chain variable region comprises an amino acid sequence selected from:
  • the light chain variable region comprises an amino acid sequence selected from:
  • the heavy chain variable region comprises an amino acid sequence selected from:
  • the light chain variable region comprises an amino acid sequence selected from:
  • amino acid sequence shown in SEQ ID NO. 6, SEQ ID NO. 10 or SEQ ID NO. 20 or an amino acid sequence having at least 75% identity to said amino acid sequence is shown in SEQ ID NO. 6, SEQ ID NO. 10 or SEQ ID NO. 20 or an amino acid sequence having at least 75% identity to said amino acid sequence.
  • At most 25% difference in amino acid sequence resulting from said "at least 75% identity” may be present in any framework region in the heavy chain variable region or light chain variable region, or in the antibodies or fragments thereof of the present invention In any domain or sequence other than the heavy chain variable region and the light chain variable region.
  • the differences may result from amino acid deletions, additions or substitutions at any position, where the substitutions may be conservative or non-conservative.
  • Said "at least 75% identity” encompasses any percentage identity between at least 75% identity and 100% identity, such as 75%, 80%, 85%, 90%, even 91%, 92%, 93% , 94%, 95%, 96%, 97%, 98%, 99%, or even 100% identity.
  • the heavy chain variable region and the light chain variable region comprise a combination of amino acid sequences selected from the following:
  • the anti-IL-11 antibody or fragment thereof of the present invention is an anti-IL-11 antibody or an antigen-binding fragment thereof.
  • the antibody is a mouse antibody, a rabbit antibody, a human antibody, a chimeric antibody or a fully or partially humanized antibody.
  • the antibody can also be a derivatized antibody, for example, an antibody obtained by CDRs transplantation, affinity maturation, point mutation transformation, chemical modification, etc. on the basis of the original murine monoclonal antibody, wherein the chemical modification includes glycosylation, Acetylation, PEGylation, phosphorylation, amidation, protease cleavage, linking with cellular ligands or effector molecules, protection and/or blocking of active reactive groups, etc.
  • the antigen-binding fragment of the anti-IL-11 antibody can be scFv, BsFv, dsFv, (dsFv) 2 , Fab, Fab', F(ab') 2 or Fv fragment of any form of the antibody.
  • the anti-IL-11 antibody or fragment thereof provided by the present invention also includes a heavy chain constant region (CH) and/or a light chain constant region (CL), preferably a human or mouse heavy chain region.
  • CH heavy chain constant region
  • CL light chain constant region
  • the antibody or fragment thereof comprises a heavy chain constant region of IgG, IgA, IgM, IgD or IgE and/or a light chain constant region of the kappa or lambda type.
  • the anti-IL-11 antibody is a monoclonal antibody, preferably are murine, chimeric or humanized monoclonal antibodies.
  • the monoclonal antibody comprises the heavy chain constant region sequence of mouse IgG1, such as shown in SEQ ID NO.3; and/or comprises the murine light chain constant region, such as shown in SEQ ID NO. 4.
  • the monoclonal antibody comprises a human heavy chain constant region and a light chain constant region, for example shown in SEQ ID NO.13 and SEQ ID NO.14, respectively.
  • the anti-IL-11 antibody of the present invention is a monoclonal antibody.
  • the anti-IL-11 antibody provided by the present invention is immunoglobulin, for example, the type of said immunoglobulin is human IgA, IgD, IgE, IgG or IgM. Further preferably, the antibody is of human IgG1 or IgG4 subtype.
  • another component is the antitumor drug.
  • anti-tumor drugs proposed by the present invention refer to drugs for the treatment of tumors, preferably cancers.
  • the antitumor drug is a drug capable of treating the following tumors or cancers: lung cancer (such as non-small cell lung cancer), breast cancer, classical Hodkin's lymphoma, gastric cancer, liver cancer (such as primary liver cancer), melanoma, d - MMR-mutated or MSI-H malignancies, cervical cancer, head and neck neoplasms (e.g., head and neck squamous cell carcinoma), urethral bladder cancer, primary mediastinal B-cell lymphoma, renal cell carcinoma, colorectal cancer, and urothelium
  • the cancer is selected from the group consisting of colorectal cancer, liver cancer, lung cancer, breast cancer, urothelial cancer, melanoma or head and neck tumors.
  • the anti-tumor drugs proposed in the present invention are immuno-oncology (IO) antibody drugs, preferably immune checkpoint inhibitors and/or agonists.
  • the anti-tumor drug is an inhibitor and/or agonist against PD-1 or PD-L1.
  • the anti-tumor drug is an anti-PD-1 or PD-L1 antibody or a fragment thereof (such as an antigen-binding fragment) or an antibody-drug conjugate targeting PD-1 or PD-L1.
  • the anti-tumor drug is an inhibitor of chemokine receptor CCR8.
  • the anti-tumor drug is an anti-CCR8 antibody or a fragment thereof (such as an antigen-binding fragment).
  • the anti-tumor drug is an anti-PD1 antibody or an anti-PD-L1 antibody.
  • the anti-PD1 antibody such as Pabolizumab (Pabolizumab), nivolumab (nivolumab), lambrolizumab, camrelizumab (Camrelizumab), tislelizumab (Tislelizumab), sintilimumab Anti-(Sintilimab), Toripalimab (Toripalimab), Serpulimab (Serpulimab), Pucotenlimab (Pucotenlimab), Penpulimab (Penpulimab), etc.
  • the anti-PD-L1 antibody such as Durvalumab, Atezolizumab (Atezolizumab), Envafolimab, Sugemalimab, etc.
  • the anti-tumor drug is an antibody against chemokine receptor CCR8, such as TPP15285 provided in the "Specific Embodiments" section of this application.
  • the anti-IL-11 antibody or its fragment and the anti-tumor drug can be administered simultaneously or sequentially.
  • the pharmaceutical combination is in the form of a pharmaceutical composition (that is, the two components are in the same system), and the anti-IL-11 antibody or its fragment is administered simultaneously with the anti-tumor drug.
  • the drug combination provided by the present invention can be used to treat tumors.
  • the tumor may be cancer, such as liver cancer or colorectal cancer.
  • the present invention provides the use of the above-mentioned drug combination comprising an anti-IL-11 antibody or a fragment thereof and an anti-tumor drug in the preparation of a drug for treating tumors.
  • the tumor is cancer.
  • the cancer is liver cancer or colorectal cancer.
  • the present invention provides the use of the above-mentioned anti-IL-11 antibody or fragment thereof in the preparation of a drug for enhancing the efficacy of an anti-tumor drug.
  • the anti-IL-11 antibody or its fragment can block or inhibit the activation of IL-11 downstream signal transduction pathway by binding to IL-11.
  • anti-IL-11 antibodies or fragments thereof are as described above.
  • the efficacy of anti-tumor drugs refers to one or more of the following conditions achieved when treating tumor-bearing subjects: delaying or inhibiting tumor growth, reducing tumor cell load or tumor burden, promote tumor regression, cause tumor shrinkage, necrosis and/or disappearance, prevent tumor recurrence, prolong the survival duration of an individual, and the like.
  • the anti-tumor drugs can cause local upregulation of IL-11 expression and/or activation of signaling pathways by killing tumor cells in the tumor microenvironment.
  • the anti-tumor drug is an immuno-oncology (IO) antibody drug, preferably an immune checkpoint inhibitor and/or agonist.
  • the anti-tumor drug is an inhibitor and/or agonist against PD-1 or PD-L1.
  • the anti-tumor drug is an anti-PD-1 or PD-L1 antibody or a fragment thereof (such as an antigen-binding fragment) or an antibody-drug conjugate targeting PD-1 or PD-L1.
  • the anti-tumor drug is an inhibitor of chemokine receptor CCR8.
  • the anti-tumor drug is an anti-CCR8 antibody or a fragment thereof (such as an antigen-binding fragment).
  • the anti-tumor drug is anti-PD1 antibody or anti-PD-L1 Antibody.
  • the anti-PD1 antibody such as Pabolizumab (Pabolizumab), nivolumab (nivolumab), lambrolizumab, camrelizumab (Camrelizumab), tislelizumab (Tislelizumab), sintilimumab Anti-(Sintilimab), Toripalimab (Toripalimab), Serpulimab (Serpulimab), Pucotenlimab (Pucotenlimab), Penpulimab (Penpulimab), etc.
  • the anti-PD-L1 antibodies are, for example, Durvalumab, Atezolizumab, Envafolimab, Sugemalimab and the like.
  • the anti-tumor drug is an antibody against chemokine receptor CCR8, such as TPP15285 provided in the "Specific Embodiments" section of this application.
  • the present invention provides the use of the anti-IL-11 antibody or fragment thereof as described above in the preparation of a medicament for use in combination with an anti-tumor drug.
  • the anti-IL-11 antibody or its fragment can block or inhibit the activation of IL-11 downstream signal transduction pathway by binding to IL-11.
  • anti-IL-11 antibodies or fragments thereof are as described above.
  • the anti-tumor drugs can cause local upregulation of IL-11 expression and/or activation of signaling pathways by killing tumor cells in the tumor microenvironment.
  • the anti-tumor drug is an immuno-oncology (IO) antibody drug, preferably an immune checkpoint inhibitor and/or agonist.
  • the anti-tumor drug is an inhibitor and/or agonist against PD-1 or PD-L1.
  • the anti-tumor drug is an anti-PD-1 or PD-L1 antibody or a fragment thereof (such as an antigen-binding fragment) or an antibody-drug conjugate targeting PD-1 or PD-L1.
  • the anti-tumor drug is an inhibitor of chemokine receptor CCR8.
  • the anti-tumor drug is an anti-CCR8 antibody or a fragment thereof (such as an antigen-binding fragment).
  • the anti-tumor drug is an anti-PD1 antibody or an anti-PD-L1 antibody.
  • the anti-PD1 antibody such as Pabolizumab (Pabolizumab), nivolumab (nivolumab), lambrolizumab, camrelizumab (Camrelizumab), tislelizumab (Tislelizumab), sintilimumab Anti-(Sintilimab), Toripalimab (Toripalimab), Serpulimab (Serpulimab), Pucotenlimab (Pucotenlimab), Penpulimab (Penpulimab), etc.
  • the anti-PD-L1 antibodies are, for example, Durvalumab, Atezolizumab, Envafolimab, Sugemalimab and the like.
  • the anti-tumor drug is an antibody against chemokine receptor CCR8, for example, the application "with TPP15285 provided in the Body Embodiments section.
  • the present invention provides a method for treating tumors, said method comprising administering to a subject in need thereof:
  • the method is used to treat a tumor, preferably a cancer.
  • a cancer preferably liver cancer or colorectal cancer.
  • the anti-tumor drugs can cause local upregulation of IL-11 expression and/or activation of signaling pathways by killing tumor cells in the tumor microenvironment.
  • the anti-IL-11 antibody or fragment thereof can block or inhibit the activation of IL-11 downstream signal transduction pathway by binding to IL-11.
  • anti-IL-11 antibodies or fragments thereof are as described above.
  • the anti-tumor drug is an immuno-oncology (IO) antibody drug, preferably an immune checkpoint inhibitor and/or agonist.
  • the anti-tumor drug is an inhibitor and/or agonist against PD-1 or PD-L1.
  • the anti-tumor drug is an anti-PD-1 or PD-L1 antibody or a fragment thereof (such as an antigen-binding fragment) or an antibody-drug conjugate targeting PD-1 or PD-L1.
  • the anti-tumor drug is an inhibitor of chemokine receptor CCR8.
  • the anti-tumor drug is an anti-CCR8 antibody or a fragment thereof (such as an antigen-binding fragment) or an antibody-drug conjugate targeting CCR8.
  • the anti-tumor drug is an anti-PD1 antibody or an anti-PD-L1 antibody.
  • the anti-PD1 antibody such as Pabolizumab (Pabolizumab), nivolumab (nivolumab), lambrolizumab, camrelizumab (Camrelizumab), tislelizumab (Tislelizumab), sintilimumab Anti-(Sintilimab), Toripalimab (Toripalimab), Serpulimab (Serpulimab), Pucotenlimab (Pucotenlimab), Penpulimab (Penpulimab), etc.
  • the anti-PD-L1 antibodies are, for example, Durvalumab, Atezolizumab, Envafolimab, Sugemalimab and the like.
  • the anti-tumor drug is an antibody against chemokine receptor CCR8, such as TPP15285 provided in the "Specific Embodiments" section of this application.
  • the subject is a mammal, preferably a primate or a rodent, more preferably a human.
  • the subject Patients with liver cancer or colorectal cancer.
  • the anti-IL-11 antibody or fragment thereof and the anti-tumor drug can be administered to the subject simultaneously or sequentially.
  • the anti-IL-11 antibody or fragment thereof and the anti-tumor drug are administered simultaneously, preferably in a drug delivery system such as a pharmaceutical composition.
  • Administration can be by parenteral administration (e.g., subcutaneous, intraperitoneal, intramuscular, intrasternal, intravenous, intraarterial, intrathecal, intraventricular, intraurethral, intracranial, intratumoral, or intrasynovial injection or infusion) ; kidney dialysis infusion; local perfusion) the anti-IL-11 antibody or its fragment and the anti-tumor drug.
  • the present invention is based on the significant synergistic effect of anti-IL-11 antibodies and other anti-tumor drugs, especially antibodies against immune checkpoint PD-1/PD-L1, and proposes two drugs targeting Combination therapy for related diseases.
  • antitumor drugs can cause upregulation of IL-11 expression or pathway activation in the tumor microenvironment by killing tumor cells, thereby reducing the level of IL-11 in the tumor microenvironment through IL-11 antibodies or Inhibiting its signaling pathway has the effect of enhancing the efficacy of anti-tumor drugs and further synergizing anti-tumor effects.
  • Figure 1 shows the analysis results of IL-11 stimulation of reporter gene expression in STAT3/IL-11RA/GP130-HEK293 cells.
  • Figure 2 shows the tumor growth of subcutaneous transplanted tumors in C57BL/6 mice bearing MC38 tumor cells, wherein 2A: tumor volume; 2B: tumor weight.
  • Figure 3 shows the tumor growth of subcutaneous transplanted tumors in C57BL/6 mice bearing Hepa 1-6 tumor cells, wherein 3A: tumor volume; 3B: tumor weight.
  • Figure 4 shows the tumor growth of subcutaneous transplanted tumors in C57BL/6 mice bearing Hepa 1-6 tumor cells, wherein 4A: tumor volume; 4B: tumor weight.
  • Figure 5 shows the tumor growth of subcutaneous xenografts in C57BL/6 mice bearing MC38-hPD-L1 tumor cells.
  • Figure 6 shows the tumor growth of subcutaneous transplanted tumors in C57BL/6 mice bearing Hepa 1-6 tumor cells, wherein 6A: tumor volume; 6B: tumor weight.
  • Figure 7 shows the tumor growth of subcutaneous xenograft tumors in Balb/C mice bearing CT26 tumor cells, where 7A: tumor volume; 7B: tumor weight.
  • Figure 8 shows the expression of B-hPD-L1 plus/hCD47 MC38 tumor cells B-Tumor growth of subcutaneous transplanted tumors in hPD-L1/hCD47/hSIRP ⁇ humanized mice, where 8A: tumor volume; 8B: tumor weight.
  • Figure 9 shows the tumor growth of subcutaneous transplanted tumors in C57BL/6 mice bearing Hepa 1-6 tumor cells, wherein 9A: tumor volume; 9B: tumor weight.
  • Figure 10 shows the tumor growth of subcutaneous xenograft tumors in C57BL/6 mice bearing MC38 tumor cells, where 10A: tumor volume; 10B: tumor weight.
  • Figure 11 shows the tumor growth of subcutaneous xenograft tumors in C57BL/6 mice bearing MC38 tumor cells, wherein 11A: tumor volume; 11B: tumor weight.
  • the present invention employs the following antibodies.
  • Anti-IL-11 antibody 3C6-mFc For the sequence, please refer to the patent publication WO2019/238882 A1;
  • Heavy chain variable region sequence (3C6-VH; SEQ ID NO.1)
  • Anti-mouse PD-1 antibody WBP336C (muWBP336c): For the sequence, please refer to the patent publication WO2019/062755A1;
  • WBP336C-VH Heavy chain variable region
  • Anti-PD-L1 mAb Atezolizumab.
  • Anti-CCR8 antibody TPP15285 see the patent publication WO2021152186A1 for the sequence;
  • WO2021152186A1 the heavy chain variable region of TPP15285 is shown in SEQ ID NO.229, and the light chain variable region is shown in SEQ ID NO.233.
  • the anti-PD-L1 light and heavy chain variable region of 2MW1531 is shown in SEQ ID NO.1/SEQ ID NO.3; the anti-CD47 light and heavy chain variable region is shown in SEQ ID NO.5/SEQ ID NO.8;
  • the chain constant region is shown in SEQ ID NO.7/SEQ ID NO.10.
  • the antibodies of the present invention are constructed using the constant regions of murine antibodies and human antibodies, respectively.
  • the following King's formula is used to calculate the q value to judge whether the combined drug has a synergistic effect:
  • E(A+B) is the tumor inhibition rate (TGI%) of the combination of the two drugs
  • EA and EB are the tumor inhibition rates of each drug alone
  • q ⁇ 1 indicates that the combination of the two drugs has an antagonistic effect
  • Drug combination has synergistic effect.
  • Embodiment 1 Obtaining of anti-IL-11 antibody
  • mice were immunized with IL-11 (Juheli, recombinant human interleukin-11 for injection, Qilu Pharmaceutical Factory, S20053046) as an immunogen.
  • the serum titer of immunized mice was detected by ELISA method, and mice with high titer were selected for shock immunization, and then spleen cells were separated and fused with myeloma cells, and cultured as single cells.
  • Take the culture supernatant for ELISA detection analyze the binding of the supernatant to human IL-11 (AAH12506.1, Pro22-Leu199), mouse IL-11 (NP_032376.1, Pro22-Leu199), and select hybridomas with good binding cell.
  • the hybridoma cells are cultured to a certain number, the cells are harvested, RNA is extracted and reverse transcription PCR is performed to obtain the light and heavy chain variable region genes of the mouse antibody and perform sequence determination.
  • the coding gene is optimized and synthesized, and the enzyme cleavage sites are designed at both ends of the coding gene; then the gene encoding the variable region of the antibody and the constant region of the heavy and light chain of the murine antibody are encoded by enzyme digestion and connection
  • the gene fragment (amino acid sequence is SEQ ID NO.3, SEQ ID NO.4) is fused and cloned into a eukaryotic transient expression vector to obtain a recombinant murine antibody expression vector.
  • the recombinant expression vector was transfected into HEK293 cells for recombinant expression, and the expression supernatant was purified using a Protein G affinity chromatography column to obtain anti-IL-11 murine antibodies mu18A10m and mu8C8m.
  • the sequences are as follows (the CDR regions are divided according to the Kabat rules, such as underlined; same below).
  • mu8C8m-VH (SEQ ID NO.7; CDRs: SEQ ID NO.29/30/31)
  • mu8C8m-VL (SEQ ID NO.8; CDRs: SEQ ID NO.32/33/34)
  • the above-mentioned murine antibodies were humanized, including transplanting the light and heavy chain CDR regions to human antibody templates with high homology, and performing necessary back mutations to obtain humanized antibody hz18A10 (heavy chain can be Variable region hz18A10-VH, shown in SEQ ID NO.9; light chain variable region hz18A10-VL, shown in SEQ ID NO.10) and hz8C8 (heavy chain variable region hz8C8-VH, shown in SEQ ID NO.11 ; light chain variable region hz8C8-VL, shown in SEQ ID NO.12). Further, using the humanized antibodies hz18A10 and hz8C8 as parent antibodies, the single-chain antibody (scFv) mutation library displayed by yeast was constructed, and mutant sequences with similar or improved affinity to the parent antibodies were obtained through sorting.
  • scFv single-chain antibody
  • variable region sequences of the obtained anti-IL-11 modified antibodies are shown in Table 1 and Table 2, respectively.
  • Anti-IL-11 antibody 3C6-hFc was used as a positive control (the heavy chain and light chain variable region sequences of 3C6-hFc are shown in SEQ ID NO.1 and SEQ ID NO.2 above).
  • the biological activity of the engineered antibody was characterized as follows.
  • the constant regions of the control antibody and the engineered antibody were human antibody heavy chain constant region SEQ ID NO.13 and light chain constant region SEQ ID NO.14.
  • the Octet QKe system instrument of Fortebio Company was used to measure the affinity of the modified antibody by using the AHC bioprobe that captures the human Fc segment to capture the Fc segment of the antibody, and the recombinantly expressed anti-IL-11 antibody 3C6-hFc at the same concentration was used as a positive control.
  • the antibody was diluted with HBS-EP+(GE) buffer, flowed through the surface of AMC probe (Cat: 18-5088, PALL), and the antibody was captured on the surface of the probe; then the human IL diluted with HBS-EP+ buffer -11 (300nM) was used as the mobile phase to react with the antibody captured on the surface of the probe.
  • the binding time was 300s and the dissociation time was 300s.
  • the response value of the blank control was deducted, and the 1:1 Langmuir binding model was fitted by software to calculate the kinetic constant of antigen-antibody binding.
  • the blocking activity of the engineered antibody on the formation of IL-11/IL-11R ⁇ /GP130 tribody complex was analyzed by competition ELISA, and the same concentration of recombinantly expressed anti-IL-11 antibody 3C6-hFc was used as a positive control.
  • IL-11R ⁇ -His (NP_004503.1, Met 1-Val 363, C-terminus-6 ⁇ His Tag) was added to the enzyme-linked plate and coated overnight; the next day to prepare samples, firstly, a fixed concentration of IL-11 (Cat: 12225-HNCE, Sino Biological) (0.4 ⁇ g/ml) and serially diluted engineered antibody (working concentration 75, 25, 8.33, 2.78, 0.926, 0.309, 0.103 ⁇ g/ml) were mixed and co-incubated, and finally gp130-hFc (NP_034690.3, Met1-Glu617, C-terminus-mFc) at a concentration of 1 ⁇ g/ml was mixed and added to the enzyme-linked plate. After co-incubation, wash and add HRP-labeled anti-human Fc secondary antibody for color development and detection.
  • HRP-labeled anti-human Fc secondary antibody for color development and detection.
  • an IL-11R ⁇ /STAT3-luc HEK293 reporter gene system was constructed.
  • the vector containing the STAT3-Luciference reporter gene system (Nanjing Kebai) was transfected, and then the stable cell line STAT3-Luc/HEK293 integrated with the STAT3-Luciference gene was obtained through pressurized screening;
  • STAT3-Luc/HEK293 integrated with the STAT3-Luciference gene was obtained through pressurized screening;
  • transfected into a vector containing the full-length human IL-11R ⁇ gene Yiqiao Shenzhou
  • a cell bank that can stably express human IL-11R ⁇ (IL-11R ⁇ /STAT3-luc HEK293Pool );
  • monoclonal isolation and screening were carried out on the cell bank to obtain IL-11R ⁇ /STAT3-luc HEK293 monoclonal, and the monoclonal that could be stably passaged was selected and preserved as a cell line.
  • the cells were seeded in a 96-well plate, and IL-11 was diluted to an appropriate concentration and serially diluted.
  • a blank well was set, added to the cells, incubated for 24 hours, and then the expression of the reporter gene was detected.
  • the color development value of all wells is subtracted from the color development value of the blank well, and the obtained data is used as reagent. volume-effect curve.
  • the results showed (FIG. 1) that IL-11 could stimulate the transcriptional expression of the reporter gene with a clear dose effect.
  • the EC50 of IL-11 stimulating the transcriptional expression of STAT3 reporter gene was 0.11ng/ml.
  • the activity of the antibody to inhibit the transcription and expression of the IL-11-stimulated cell reporter gene was detected. Seed the cells in a 96-well plate, dilute IL-11 to 0.3ng/ml, and incubate with serially diluted antibody (10 ⁇ g/ml, 3-fold serial dilution of 10 gradients) for 30 minutes, then add to the cells and incubate for 6 hours , and then add the detection reagent in the Luciferase assay kit (Novizan, D1201-02bio-lite) and read the signal value (RLUsample).
  • Inhibition % (RLUhigh-RLUsample)/(RLUhigh-RLUlow) ⁇ 100%
  • the dose-effect curve was drawn using the GraphPad Prism 9 four-parameter formula to obtain the IC50 value of each antibody.
  • 6-week-old female C57BL/6 mice (Speyford (Beijing) Biotechnology Co., Ltd.) were subcutaneously inoculated with 3 ⁇ 10 6 MC38 mouse colon cancer cells, and were randomly divided into groups when the tumor grew to about 70 mm 3 .
  • Only/group, grouping and administration dosage, frequency are as table 6, every week intraperitoneal administration twice (when adopting two kinds of reagents, be administration at the same time, hereinafter the same), administration 3 times altogether, administration is measured simultaneously Tumor volume and mouse weight, when the weight of the mice decreased by more than 15%, or when the tumor volume of a single animal exceeded 3000mm3 or the average tumor volume of a group of animals exceeded 2000mm3 , the experiment on the relevant mice was stopped, and the mice were euthanized. The results are shown in Figure 2.
  • the anti-IL-11 antibodies mu8C8 and WBP336C are constructed using mouse heavy chain and light chain constant regions (SEQ ID NO.3 and SEQ ID NO.4), wherein the heavy chain and light chain variable region sequences of mu8C8 are shown in SEQ ID Shown in NO.15 and SEQ ID NO.17; Same below.
  • the tumor inhibition rate of each group is shown in Figure 2A, and the q value was calculated according to King's formula>1.
  • Example 4 The therapeutic effect of anti-IL-11 antibody combined with anti-PD-1 antibody in liver cancer
  • mice body weight when the mouse body weight drops by more than 15%, or the tumor volume of a single animal exceeds 3000mm 3 or a When the average tumor volume of animals in the same group exceeds 2000 mm 3 , the experiment on the relevant mice is stopped, and the mice are euthanized. The results are shown in Figure 3.
  • the anti-IL-11 antibody mu18A10 was constructed using mouse heavy chain and light chain constant regions (SEQ ID NO.3 and SEQ ID NO.4), and its heavy chain and light chain variable region sequences were as shown in SEQ ID NO.19 and Shown in SEQ ID NO.20; Same below.
  • the tumor inhibition rate of each group is shown in Figure 3A, and the q value was calculated according to King's formula>1.
  • anti-PD-1 antibody showed dose-dependent anti-tumor efficacy, when anti-PD-1 antibody was combined with 20 mg/kg
  • the combination of anti-IL-11 antibodies showed a synergistic anti-tumor effect, and this synergistic anti-tumor effect showed a synergistic effect when different doses of anti-PD-1 antibodies were used in combination.
  • the tumor inhibition rate of each group is shown in Figure 4A, and the q value was calculated according to King's formula>1.
  • the tumor inhibition rate of each group is shown in Figure 5, and the q value was calculated according to King's formula>1.
  • 6-week-old male C57BL/6 mice (Jiangsu Jicui Yaokang Biotechnology Co., Ltd.) were subcutaneously inoculated with 1 ⁇ 106 Hepa 1-6 mouse liver cancer cells, and were randomly divided into groups when the tumors grew to about 49mm3. 6 mice/group, the grouping, dosage and frequency of administration are shown in Table 10, and each group was administered intraperitoneally twice a week, for a total of 4 administrations. The tumor volume and the weight of the mice were measured at the same time as the administration.
  • mice When the weight of the mice dropped by more than 15 %, or when the tumor volume of a single animal exceeds 3000mm3 or the average tumor volume of a group of animals exceeds 2000mm3, the experiment on the relevant mice is stopped, and the mice are euthanized. The results are shown in Figure 6.
  • the anti-IL-11 antibody mu8C8F was constructed using mouse heavy chain and light chain constant regions (SEQ ID NO.3 and SEQ ID NO.4), wherein the heavy chain and light chain variable region sequences of mu8C8F are shown in SEQ ID NO. Shown in 16 and SEQ ID NO.18; Same below.
  • the tumor inhibition rate of each group is shown in Fig. 6A, and the q value was calculated according to King's formula > 1.
  • 6-week-old male Balb/C mice (Jiangsu Jicui Yaokang Biotechnology Co., Ltd.) were subcutaneously inoculated with 5 ⁇ 10 5 CT26 mouse colon cancer cells.
  • the tumors grew to about 72 mm 3 , they were randomly divided into 6 groups. / group, grouping and administration dosage, frequency are shown in Table 11, and each group is intraperitoneally administered twice a week, and is administered 4 times in total, and the tumor volume and mouse body weight are measured at the same time as the administration, when the mouse body weight drops more than 15%.
  • the tumor volume of a single animal exceeds 3000mm3 or the average tumor volume of a group of animals exceeds 2000mm3, stop the experiment on the relevant mice, and give the mice euthanasia.
  • the results are shown in Figure 7.
  • the tumor inhibition rate of each group is shown in Fig. 7A, and the q value was calculated according to King's formula > 1.
  • the tumor inhibition rate of each group is shown in Figure 8A, and the q value was calculated according to King's formula>1.
  • 6-week-old male C57BL/6 mice (Jiangsu Jicui Yaokang Biotechnology Co., Ltd.) were subcutaneously inoculated with 5 ⁇ 10 6 Hepa 1-6 mouse liver cancer cells, and were randomly divided into groups when the tumors grew to about 50 mm 3 .
  • 6 mice/group the grouping, dosage and frequency of administration are shown in Table 13, and each group was intraperitoneally administered twice a week for a total of 3 times, and the tumor volume and mouse weight were measured at the same time. %, or when the tumor volume of a single animal exceeds 3000mm3 or the average tumor volume of a group of animals exceeds 2000mm3, the experiment on the relevant mice is stopped, and the mice are euthanized. The results are shown in Figure 9.
  • the anti-IL-11 antibody hz8C8F is constructed using human heavy chain and light chain constant regions (SEQ ID NO.13 and SEQ ID NO.14), wherein the sequences of the heavy chain and light chain variable regions of hz8C8F are shown in SEQ ID NO. Shown in 15 and SEQ ID NO.17; Same below.
  • the tumor inhibition rate of each group is shown in Fig. 9A, and the value of q>1 was calculated according to King's formula.
  • Example 11 The therapeutic effect of anti-IL-11 antibody combined with anti-CCR8 antibody in colon cancer
  • 6-week-old female C57BL/6 mice (Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.) were subcutaneously inoculated with 3 ⁇ 10 6 MC38 mouse colon cancer cells. When the tumor grew to about 70 mm 3 , they were randomly divided into groups. Only/group, grouping, dosage and frequency of administration are shown in Table 14. Each group is administered intraperitoneally twice a week, 4 times in total, and the tumor volume and mouse weight are measured at the same time. When the mouse body weight drops by more than 15% or the tumor volume of a single animal exceeds 3000mm3 or the average tumor volume of a group of animals exceeds 2000mm3 . The experiments on the relevant mice were terminated and the mice were euthanized. The results are shown in Figure 10.
  • the anti-CCR8 antibody TPP15285 was constructed using human heavy chain and light chain constant regions (SEQ ID NO.13 and SEQ ID NO.14).
  • the tumor inhibition rate of each group is shown in Fig. 10A, and the q value was calculated according to King's formula > 1.
  • Example 12 The therapeutic effect of anti-IL-11 antibody combined with anti-PD1 antibody in colon cancer
  • 6-week-old female C57BL/6 mice (Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.) were subcutaneously inoculated with 3 ⁇ 10 6 MC38 mouse colon cancer cells.
  • the tumor grew to about 150mm3, they were randomly divided into groups, 6 mice / group, grouping and administration dosage, frequency are shown in Table 15, and each group is intraperitoneally administered twice a week, and is administered 3 times in total, and the tumor volume and mouse body weight are measured at the same time as the administration, when the mouse body weight drops more than 15%.
  • the experiment on the relevant mice is stopped, and the mice are euthanized. The results are shown in Figure 11.
  • the anti-IL-11 antibody hz18A10F is constructed using human heavy chain and light chain constant regions (SEQ ID NO.13 and SEQ ID NO.14), wherein the sequences of the heavy chain and light chain variable regions of hz18A10F are shown in SEQ ID NO. 19 and shown in SEQ ID NO.20.
  • the tumor inhibition rate of each group is shown in Fig. 11A.
  • the q value of the combination of hz8C8F and muWBP336c calculated according to the King's formula was >1, while the q value of the combination of hz18A10F and muWBP336c was ⁇ 1.

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Abstract

La présente invention concerne une combinaison de médicaments pour le traitement de tumeurs. La combinaison de médicaments comprend : un anticorps anti-IL-11 ou un fragment de celui-ci ; et un médicament antitumoral, le médicament antitumoral pouvant provoquer une régulation positive de l'expression d'IL-11 locale et/ou une activation de la voie de signalisation dans un micro-environnement tumoral par destruction de cellules tumorales. La présente invention concerne également un procédé d'administration de médicament synergique pour l'anticorps anti-IL-11 ou son fragment et le médicament antitumoral.
PCT/CN2023/073746 2022-01-29 2023-01-29 Polythérapie antitumorale utilisant un anticorps anti-il-11 WO2023143590A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180186872A1 (en) * 2016-12-16 2018-07-05 Singapore Health Services Pte Ltd. Il-11ra antibodies
CN113651888A (zh) * 2020-08-13 2021-11-16 广东东阳光药业有限公司 Il-11的抗体及其应用
WO2022013300A1 (fr) * 2020-07-14 2022-01-20 Fundación Del Sector Público Estatal Centro Nacional De Investigaciones Oncológicas Carlos III (F.S.P. CNIO) Anticorps neutralisant la sous-unité alpha du récepteur de l'interleukine 11 (il11ra) et leurs utilisations
CN113980129A (zh) * 2021-01-15 2022-01-28 东大生物技术(苏州)有限公司 一组il-11单克隆抗体及其医药用途

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Publication number Priority date Publication date Assignee Title
US20180186872A1 (en) * 2016-12-16 2018-07-05 Singapore Health Services Pte Ltd. Il-11ra antibodies
WO2022013300A1 (fr) * 2020-07-14 2022-01-20 Fundación Del Sector Público Estatal Centro Nacional De Investigaciones Oncológicas Carlos III (F.S.P. CNIO) Anticorps neutralisant la sous-unité alpha du récepteur de l'interleukine 11 (il11ra) et leurs utilisations
CN113651888A (zh) * 2020-08-13 2021-11-16 广东东阳光药业有限公司 Il-11的抗体及其应用
CN113980129A (zh) * 2021-01-15 2022-01-28 东大生物技术(苏州)有限公司 一组il-11单克隆抗体及其医药用途

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Title
KORTEKAAS ROSA K.; BURGESS JANETTE K.; VAN ORSOY ROEL; LAMB DAVID; WEBSTER MEGAN; GOSENS REINOUD: "Therapeutic Targeting of IL-11 for Chronic Lung Disease", TRENDS IN PHARMACOLOGICAL SCIENCES., ELSEVIER, HAYWARTH., GB, vol. 42, no. 5, 15 April 2021 (2021-04-15), GB , pages 354 - 366, XP086538783, ISSN: 0165-6147, DOI: 10.1016/j.tips.2021.01.007 *

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