WO2024085726A1 - Composition anticancéreuse comprenant un anticorps anti-vsig4 - Google Patents

Composition anticancéreuse comprenant un anticorps anti-vsig4 Download PDF

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WO2024085726A1
WO2024085726A1 PCT/KR2023/016397 KR2023016397W WO2024085726A1 WO 2024085726 A1 WO2024085726 A1 WO 2024085726A1 KR 2023016397 W KR2023016397 W KR 2023016397W WO 2024085726 A1 WO2024085726 A1 WO 2024085726A1
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amino acid
acid sequence
cancer
represented
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Korean (ko)
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권병세
이중원
김혜정
강경정
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주식회사 유틸렉스
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    • 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
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • 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
    • 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
    • C07K16/28—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
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2827—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
    • 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
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • 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
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C07K2317/734—Complement-dependent cytotoxicity [CDC]

Definitions

  • the present invention provides a composition for preventing or treating cancer comprising a humanized anti-VSIG4 antibody or binding fragment thereof; and a composition that additionally contains an anti-PD-L1 antibody and exhibits a significant cancer prevention or treatment effect.
  • GLOBOCAN 2020 produced by the International Agency for Research on Cancer, estimates that there were approximately 19.3 million new cancer cases (18.1 million excluding non-melanoma skin cancer) and nearly 10 million cancer deaths (excluding non-melanoma skin cancer) worldwide in 2020. It is reported that 9.9 million people (excluding non-melanoma skin cancer) occurred.
  • Cancer treatment technology has continued to develop, but existing treatment methods all have limitations. In order to determine the need for developing new treatments, it is necessary to establish a comprehensive strategy that considers the survival rate for each cancer type.
  • Immunotherapy which is currently undergoing active research and development, is expected to minimize the side effects of existing treatments by strengthening the immune system of cancer patients and allowing the body to destroy cancer cells on its own.
  • more than 70% of patients show resistance to immunotherapy, making it difficult to expect a therapeutic effect.
  • One of the reasons for this low treatment effect is that the tumor microenvironment is not taken into consideration, so recent anticancer drug treatment is approached with a strategy that takes the tumor microenvironment into consideration.
  • the tumor micro-environment is favorable for tumor growth and metastasis.
  • the tumor microenvironment is well known to have suppressed immune function and metabolic stress, which acts as a major obstacle to anticancer treatment.
  • the tumor microenvironment is classified as “cold” or “hot” depending on the degree of T cell infiltration. Hot tumors are infiltrated with T cells and are immune activated, whereas cold tumors are characterized by the absence or exclusion of T cells. In these cold tumors, it is difficult for effector immune cells to infiltrate and resistance to various immune checkpoint inhibitors (ICIs) appears.
  • ICIs immune checkpoint inhibitors
  • One of the reasons why many immune checkpoint inhibitors that have been attempted previously have low actual therapeutic effects is because they do not take into account the tumor microenvironment. Therefore, to increase the response rate to immunotherapy, removal or reprogramming of the abnormal tumor microenvironment that converts noninflamed cold tumors into hot tumors can be an important anticancer treatment approach.
  • Tumor-associated macrophages a specific type of macrophage found in the tumor microenvironment, are known to be important cells that create a chronic inflammatory state in cancer.
  • Tumor-related macrophages migrate to tumor tissues in response to tumor-related inflammation and, unlike other common macrophages, lack cytokine activity.
  • Tumor-related macrophages secrete immune regulatory cytokines such as IL-4, IL-13, and IL-10, and vascular endothelial growth factor (VEGF), which promotes angiogenesis and epidermal growth that helps tumor growth. It has been reported that epidermal growth factor (EGF) is also secreted. For this reason, since the increase in tumor-related macrophages is directly related to the poor prognosis of cancer, there is a need for new anticancer treatments targeting tumor-related macrophages.
  • cytokines such as IL-4, IL-13, and IL-10
  • VEGF vascular endothelial growth factor
  • VSIG4 (V-set immunoglobulin-domain-containing 4) is mainly expressed in tissue-resident macrophages (M2 type macrophages), especially Kupffer cells in liver tissue.
  • M2 type macrophages tissue-resident macrophages
  • VSIG4 is expressed in tumor-associated macrophages (TAM), which inhibits the proliferation of antigen-specific T cells, suppresses inflammatory cytokine production, and induces proteins involved in immune tolerance. This creates a favorable environment for tumors. It is associated with worse survival in carcinomas showing increased VSIG4 expression, such as non-small cell lung cancer (NSCLC), multiple myeloma, ovarian cancer, and glioma. This suggests that VSIG4 plays an important role in tumor immune evasion.
  • NSCLC non-small cell lung cancer
  • the present inventors While researching a new anticancer agent that can improve the tumor-related microenvironment, the present inventors discovered that the anti-VSIG4 antibody of the present invention, which targets VSIG4, which plays an important role in tumor immune evasion, was found to have antibody-dependent cytotoxicity (Antibody-Dependent Cellular). It was confirmed that it can have the effect of improving the tumor microenvironment without showing cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), especially when administered in combination with anti-PD-L1 antibody. The present invention was completed after confirming that it can exhibit excellent anti-cancer effects.
  • ADCC cytotoxicity
  • CDC complement-dependent cytotoxicity
  • the object of the present invention is a heavy chain CDR1 represented by the amino acid sequence of SEQ ID NO: 1, a heavy chain CDR2 represented by the amino acid sequence of SEQ ID NO: 2, and a heavy chain CDR3 represented by the amino acid sequence of SEQ ID NO: 3; and light chain CDR1 represented by the amino acid sequence of SEQ ID NO: 4, light chain CDR2 represented by the amino acid sequence of SEQ ID NO: 5, and light chain CDR3 represented by the amino acid sequence of SEQ ID NO: 6;
  • a pharmaceutical composition for preventing or treating cancer containing a humanized anti-VSIG4 antibody or an antigen-binding fragment thereof, or an adjuvant anti-cancer treatment for enhancing the efficacy of an anti-PD-L1 antibody is a pharmaceutical composition for preventing or treating cancer containing a humanized anti-VSIG4 antibody or an antigen-binding fragment thereof, or an adjuvant anti-cancer treatment for enhancing the efficacy of an anti-PD-L1 antibody.
  • the object of the present invention is a) heavy chain CDR1 represented by the amino acid sequence of SEQ ID NO: 1, heavy chain CDR2 represented by the amino acid sequence of SEQ ID NO: 2, and heavy chain CDR3 represented by the amino acid sequence of SEQ ID NO: 3; and light chain CDR1 represented by the amino acid sequence of SEQ ID NO: 4, light chain CDR2 represented by the amino acid sequence of SEQ ID NO: 5, and light chain CDR3 represented by the amino acid sequence of SEQ ID NO: 6;
  • the present invention provides a) heavy chain CDR1 represented by the amino acid sequence of SEQ ID NO: 1, heavy chain CDR2 represented by the amino acid sequence of SEQ ID NO: 2, and heavy chain CDR3 represented by the amino acid sequence of SEQ ID NO: 3; and light chain CDR1 represented by the amino acid sequence of SEQ ID NO: 4, light chain CDR2 represented by the amino acid sequence of SEQ ID NO: 5, and light chain CDR3 represented by the amino acid sequence of SEQ ID NO: 6; A humanized anti-VSIG4 antibody or antigen-binding fragment thereof comprising; and b) an anti-PD-L1 antibody.
  • the present invention provides a) heavy chain CDR1 represented by the amino acid sequence of SEQ ID NO: 1, heavy chain CDR2 represented by the amino acid sequence of SEQ ID NO: 2, and heavy chain CDR3 represented by the amino acid sequence of SEQ ID NO: 3; and light chain CDR1 represented by the amino acid sequence of SEQ ID NO: 4, light chain CDR2 represented by the amino acid sequence of SEQ ID NO: 5, and light chain CDR3 represented by the amino acid sequence of SEQ ID NO: 6; A humanized anti-VSIG4 antibody or antigen-binding fragment thereof comprising; and b) an anti-PD-L1 antibody, and provides a combination administration agent for preventing or treating cancer.
  • the present invention provides a) heavy chain CDR1 represented by the amino acid sequence of SEQ ID NO: 1, heavy chain CDR2 represented by the amino acid sequence of SEQ ID NO: 2, and heavy chain CDR3 represented by the amino acid sequence of SEQ ID NO: 3; and light chain CDR1 represented by the amino acid sequence of SEQ ID NO: 4, light chain CDR2 represented by the amino acid sequence of SEQ ID NO: 5, and light chain CDR3 represented by the amino acid sequence of SEQ ID NO: 6;
  • the present invention provides a heavy chain CDR1 represented by the amino acid sequence of SEQ ID NO: 1, a heavy chain CDR2 represented by the amino acid sequence of SEQ ID NO: 2, and a heavy chain CDR3 represented by the amino acid sequence of SEQ ID NO: 3; and light chain CDR1 represented by the amino acid sequence of SEQ ID NO: 4, light chain CDR2 represented by the amino acid sequence of SEQ ID NO: 5, and light chain CDR3 represented by the amino acid sequence of SEQ ID NO: 6;
  • an adjuvant anti-cancer treatment for enhancing the efficacy of an anti-PD-L1 antibody, comprising a humanized anti-VSIG4 antibody or an antigen-binding fragment thereof.
  • the present invention provides a) heavy chain CDR1 represented by the amino acid sequence of SEQ ID NO: 1, heavy chain CDR2 represented by the amino acid sequence of SEQ ID NO: 2, and heavy chain CDR3 represented by the amino acid sequence of SEQ ID NO: 3; and light chain CDR1 represented by the amino acid sequence of SEQ ID NO: 4, light chain CDR2 represented by the amino acid sequence of SEQ ID NO: 5, and light chain CDR3 represented by the amino acid sequence of SEQ ID NO: 6; A humanized anti-VSIG4 antibody or antigen-binding fragment thereof comprising; and b) administering an anti-PD-L1 antibody to a subject.
  • the present invention provides a) heavy chain CDR1 represented by the amino acid sequence of SEQ ID NO: 1, heavy chain CDR2 represented by the amino acid sequence of SEQ ID NO: 2, and heavy chain CDR3 represented by the amino acid sequence of SEQ ID NO: 3; and light chain CDR1 represented by the amino acid sequence of SEQ ID NO: 4, light chain CDR2 represented by the amino acid sequence of SEQ ID NO: 5, and light chain CDR3 represented by the amino acid sequence of SEQ ID NO: 6;
  • a method for enhancing the efficacy of an anti-PD-L1 antibody comprising administering to a subject a humanized anti-VSIG4 antibody or antigen-binding fragment thereof.
  • the humanized anti-VSIG4 antibody or antigen-binding fragment thereof of the present invention can exhibit an anti-cancer effect by regulating immune cells in the human body and improving the microenvironment of cancer tissue, and when administered together with an anti-PD-L1 antibody, it has a significant anti-cancer effect. It can be expressed. Therefore, the present invention can be used in various cancer prevention or treatment fields, especially in the prevention or treatment of cancer types that have a poor prognosis with respect to immune checkpoint inhibitor therapy.
  • 1 is a schematic diagram of the conversion analysis method performed in the present invention.
  • Figure 2 shows the results of analysis of the binding activity of EU103 to HeLa-hVSIG4 cells, a cell line overexpressing VSIG4.
  • Figure 3 is a diagram showing the results of confirming the expression of VSIG4 in anti-inflammatory macrophages and the expression of VSIG4 in differentiated anti-inflammatory macrophages through FACS analysis.
  • Figure 4 shows the results of confirming the binding activity of EU103 to VSIG4 of anti-inflammatory macrophages.
  • Figure 5 is a diagram showing the results of evaluating the ADCC activity of EU103 in HeLa cells, a cell line overexpressing VSIG4 (EU103-IgG1: introduction of wild-type IgG1).
  • Figure 6 is a diagram showing the results of confirming the binding between EU103 and C1q through enzyme-linked immunosorbent assay (ELISA) (EU103-IgG1: introduction of wild-type IgG1).
  • ELISA enzyme-linked immunosorbent assay
  • Figure 7 is a diagram showing the results of confirming the proliferation of CD4 + / CD8 + T cells according to EU103 treatment concentration.
  • Figure 8 is a diagram showing the results confirming the conversion effect of EU103 in tumor-related macrophages isolated from ovarian cancer patients.
  • Figure 9 is a diagram showing the results confirming the tumor growth inhibition effect upon EU103 administration in the PBMC humanized mouse A549-luci tumor orthotopic model.
  • Figure 10 shows the results of a toxicity test confirming Kupffer cell depletion following treatment with EU103.
  • Figure 11 is a diagram showing the results of confirming changes in cytokine and arginase levels in Kupffer cells (hKC), TAM, and M2 macrophages according to EU103 treatment.
  • Figure 12 is a diagram showing the results confirming the tumor growth inhibition effect upon co-administration of EU103 and Tecentriq in the PBMC humanized mouse A549-luci tumor orthotopic model (A, B: Confirmation of tumor size change in the mouse model, C) : Tumor size measurement on the 43rd day after the end of the experiment).
  • the present invention provides a) heavy chain CDR1 represented by the amino acid sequence of SEQ ID NO: 1, heavy chain CDR2 represented by the amino acid sequence of SEQ ID NO: 2, and heavy chain CDR3 represented by the amino acid sequence of SEQ ID NO: 3; and light chain CDR1 represented by the amino acid sequence of SEQ ID NO: 4, light chain CDR2 represented by the amino acid sequence of SEQ ID NO: 5, and light chain CDR3 represented by the amino acid sequence of SEQ ID NO: 6; A humanized anti-VSIG4 antibody or antigen-binding fragment thereof comprising; or
  • heavy chain CDR1 represented by the amino acid sequence of SEQ ID NO: 1
  • heavy chain CDR2 represented by the amino acid sequence of SEQ ID NO: 2
  • heavy chain CDR3 represented by the amino acid sequence of SEQ ID NO: 3
  • light chain CDR1 represented by the amino acid sequence of SEQ ID NO: 4
  • light chain CDR2 represented by the amino acid sequence of SEQ ID NO: 5
  • light chain CDR3 represented by the amino acid sequence of SEQ ID NO: 6
  • a humanized anti-VSIG4 antibody or antigen-binding fragment thereof comprising comprising
  • b) comprising an anti-PD-L1 antibody comprising an anti-PD-L1 antibody
  • It relates to a pharmaceutical composition for preventing or treating cancer.
  • the humanized anti-VSIG4 antibody or antigen-binding fragment thereof of the present invention may include a heavy chain variable region represented by SEQ ID NO: 7 and/or a light chain variable region represented by SEQ ID NO: 8.
  • the hydrophobic index of the amino acid may be considered.
  • Each amino acid is assigned a hydrophobicity index based on its hydrophobicity and charge: isoleucine (+4.5); Valine (+4.2); leucine (+3.8); phenylalanine (+2.8); Cysteine/Cysteine (+2.5); Methionine (+1.9); Alanine (+1.8); Glycine (-0.4); threonine (-0.7); Serine (-0.8); Tryptophan (-0.9); Tyrosine (-1.3); Proline (-1.6); histidine (-3.2); glutamate (-3.5); Glutamine (-3.5); Aspartate (-3.5); Asparagine (-3.5); Lysine (-3.9); and arginine (-4.5).
  • the hydrophobic amino acid index is very important in imparting interactive biological functions to proteins or peptides. It is a known fact that similar biological activity can be maintained only when substituted with an amino acid having a similar hydrophobicity index.
  • substitution is made between amino acids showing a difference in the hydrophobicity index, preferably within ⁇ 2, more preferably within ⁇ 1, and even more preferably within ⁇ 0.5.
  • hydrophilicity values are assigned to each amino acid residue: arginine (+3.0); Lysine (+3.0); Asphaltate (+3.0 ⁇ 1); glutamate (+3.0 ⁇ 1); Serine (+0.3); Asparagine (+0.2); Glutamine (+0.2); Glycine (0); threonine (-0.4); Proline (-0.5 ⁇ 1); Alanine (-0.5); histidine (-0.5); Cysteine (-1.0); Methionine (-1.3); Valine (-1.5); leucine (-1.8); isoleucine (-1.8); Tyrosine (-2.3); Phenylalanine (-2.5); Tryptophan (-3.4).
  • substitution is made between amino acids showing a difference in hydrophilicity value, preferably within ⁇ 2, more preferably within ⁇ 1, and even more preferably within ⁇ 0.5.
  • Amino acid exchanges in peptides that do not overall alter the activity of the molecule are known in the art.
  • the most common exchanges are amino acid residues Ala/Ser, Val/Ile, Asp/Glu, Thr/Ser, Ala/Gly, Ala/Thr, Ser/Asn, Ala/Val, Ser/Gly, Tyr/Phe, Ala/ It is an exchange between Pro, Lys/Arg, Asp/Asn, Leu/Ile, Leu/Val, Ala/Glu, and Asp/Gly.
  • amino acid sequences represented by SEQ ID NOs: 1 to 9 of the present invention are interpreted to also include sequences showing substantial identity with the sequences described in the sequence listing.
  • the above substantial identity is obtained by aligning the amino acid sequences represented by SEQ ID NOs. 1 to 9 of the present invention and any other sequences to correspond as much as possible, and analyzing the aligned sequences using an algorithm commonly used in the art.
  • sequences showing at least 80% or more homology more preferably 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more. it means.
  • any method known in the art can be used without limitation.
  • the antigen-binding fragment is Fab, Fab', (Fab') 2 , Fv, scFv (single chain sc), bis-scFv, scFv-Fc fragment, Fab 2 , Fab 3 , minibody, dia. It may be selected from the group consisting of sieve, triase, tetrasieve and nanosieve. Said fragment has at least one of the characteristic CDRs of the antibody according to the invention.
  • Fab has a structure comprising the variable regions of the light and heavy chains, the constant region of the light chain, and the first constant region of the heavy chain, and has one antigen binding site.
  • Fab' differs from Fab in having a hinge containing one or more cysteine residues at the C-terminus of the heavy chain CH1 domain.
  • F(ab)' antibodies are produced because cysteine residues in the hinge region of Fab' form disulfide bonds.
  • Fv is the smallest antibody fragment with only the heavy and light chain variable regions.
  • dsFv double-chain Fv
  • ssFv single-chain Fv
  • antibody fragments can be obtained using proteinases (e.g., Fab can be obtained by restriction digestion of the whole antibody with papain, and F(ab)' fragments can be obtained by restriction digestion with pepsin. can be), preferably it can be produced by genetic engineering techniques.
  • the "antigen-binding fragment” will consist of or comprise a partial sequence of the heavy or light chain variable chain of the antibody from which it is derived, said partial sequence having the same binding specificity with respect to the target as the antibody from which it is derived. and sufficient affinity, preferably at least equal to 1/100, more preferably at least 1/10, of the affinity of the antibody from which it is derived.
  • the whole humanized anti-VSIG4 antibody of the invention may include subtypes or variants of IgA, IgD, IgE, IgM and IgG, and may particularly include IgG1.
  • Heavy chain constant regions are of gamma ( ⁇ ), mu ( ⁇ ), alpha ( ⁇ ), delta ( ⁇ ), and epsilon ( ⁇ ) types and subclasses gamma 1 ( ⁇ 1), gamma 2 ( ⁇ 2), gamma 3 ( ⁇ 3); It has gamma 4 ( ⁇ 4), alpha 1 ( ⁇ 1) and alpha 2 ( ⁇ 2).
  • the constant region of the light chain may include the kappa ( ⁇ ) and lambda ( ⁇ ) types.
  • the humanized anti-VSIG4 antibody of the present invention may include the Fc sequence of a human IgG1 antibody.
  • the humanized anti-VSIG4 antibody of the present invention may be an antibody with an improved Fc region that regulates antibody function, and may exhibit IgG1 Fc antibody dependent cellular cytotoxicity (ADCC) and complement dependent cytotoxicity (ADCC). CDC) can be characterized as being suppressed. Accordingly, the humanized anti-VSIG4 antibody of the present invention is characterized by comprising an engineered IgG1 Fc region represented by SEQ ID NO: 9, and is at least about 80%, 85%, 90%, 95%, 96%, 97% thereof. , 98%, or 99% or more sequence identity may be included. wherein the variants include additions, deletions, and/or substitutions.
  • the humanized anti-VSIG4 antibody of the present invention does not exhibit toxicity to Kupffer cells, and exhibits very low antibody-dependent cytotoxicity and complement-dependent cytotoxicity due to the removal of the binding ability to Fc ⁇ R and C1q, and at the same time, T It can promote cell proliferation and convert tumor-associated macrophages (TAMs) into inflammatory macrophages that suppress tumors. As a result, the tumor microenvironment can be improved and excellent anticancer effects are achieved.
  • the humanized anti-VSIG4 antibody of the present invention can convert a noninflamed cold tumor into a hot tumor and remove the abnormal tumor microenvironment, effectively improving the treatment response to anticancer immunotherapy agents.
  • the present invention provides a composition for preventing or treating cancer further comprising an anti-PD-L1 antibody.
  • a humanized anti-VSIG4 antibody or binding fragment thereof of the invention and a cancer prevention or pharmaceutical composition containing an anti-PD-L1 antibody, or a combined administration agent for cancer prevention or treatment exhibits a significantly increased anticancer effect compared to the administration of an anti-VSIG4 antibody or a binding fragment thereof or an anti-PD-L1 antibody alone. You can.
  • Combination therapy refers to a situation in which a subject is simultaneously exposed to two or more therapeutic regimens (e.g., two or more therapeutic agents).
  • a humanized anti-VSIG4 antibody or binding fragment thereof; and anti-PD-L1 antibody can be administered simultaneously.
  • the humanized anti-VSIG4 antibody or antigen-binding fragment thereof; and anti-PD-L1 antibody may be administered sequentially.
  • the anti-PD-L1 antibody that can be administered in combination with the humanized anti-VSIG4 antibody or binding fragment thereof simultaneously or sequentially may include, without limitation, antibodies known in the art, and includes antigen-binding fragments thereof. However, it may preferably be atezolizumab, durvalumab, or avelumab, and in a preferred embodiment of the present invention, atezolizumab (Tecentriq) was used to confirm the effect.
  • Cancer of the present invention can be used interchangeably with tumor, neoplasm, and carcinoma, and includes a humanized anti-VSIG4 antibody or binding fragment thereof; Alternatively, it may include, without limitation, cancer species that can exhibit anti-cancer effects by humanized anti-VSIG4 antibody or binding fragment thereof and anti-PD-L1 antibody.
  • the cancer of the present invention may preferably be a VSIG4-overexpressing cancer, for example, multiple myeloma, ovarian cancer, lung cancer, non-small cell lung cancer, glioma, breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, fallopian tube cancer, gallbladder cancer.
  • stomach cancer head and neck cancer
  • blood cancer laryngeal cancer
  • liver cancer lymphoma
  • melanoma mesothelioma
  • primary peritoneal cancer salivary gland cancer
  • sarcoma thyroid cancer
  • pancreatic cancer renal cell carcinoma
  • glioblastoma and prostate cancer. It could be more than that.
  • humanized anti-VSIG4 antibody or antigen-binding fragment thereof of the present invention when administered in combination with the anti-PD-L1 antibody, they may be included or administered in the composition at 1:1 to 5 (w/w)%, preferably Can be contained or administered in a ratio of 1:1 to 3 (w/w)%, or 1:1 (w/w)%.
  • the present invention provides a) heavy chain CDR1 represented by the amino acid sequence of SEQ ID NO: 1, heavy chain CDR2 represented by the amino acid sequence of SEQ ID NO: 2, and heavy chain CDR3 represented by the amino acid sequence of SEQ ID NO: 3; and light chain CDR1 represented by the amino acid sequence of SEQ ID NO: 4, light chain CDR2 represented by the amino acid sequence of SEQ ID NO: 5, and light chain CDR3 represented by the amino acid sequence of SEQ ID NO: 6; A humanized anti-VSIG4 antibody or antigen-binding fragment thereof comprising; and b) administering an anti-PD-L1 antibody to a subject.
  • administration generally refers to administering a composition to an entity or system to deliver the agent contained in or contained within the composition.
  • administration may be ocular, buccal, parenteral, topical, etc.
  • administration may be or include one or more of the following: bronchial (e.g., via bronchial instillation), buccal, dermal (e.g., dermal, intradermal, intradermal, transdermal, etc.
  • administration may involve only a single dose. In some embodiments, administration may involve applying a fixed number of doses.
  • administration may include intermittent (e.g., multiple doses spaced over time) administration and/or periodic (e.g., individual doses separated by a regular period of time) dosing.
  • administration may involve continuous doses (e.g., infusion) for at least a selected period of time.
  • the pharmaceutical composition according to the present invention may include a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers include binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, colorants, flavorings, etc. for oral administration.
  • buffers, preservatives, and analgesics can be used.
  • Topics, solubilizers, isotonic agents, stabilizers, etc. can be mixed and used, and for topical administration, bases, excipients, lubricants, preservatives, etc. can be used.
  • the dosage form of the pharmaceutical composition according to the present invention can be prepared in various ways by mixing it with a pharmaceutically acceptable carrier as described above.
  • oral administration it can be manufactured in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and in the case of injections, it can be manufactured in the form of unit dosage ampoules or multiple dosage forms. there is.
  • examples of carriers, excipients and diluents suitable for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or mineral oil may be used.
  • fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives, etc. may be additionally included.
  • the pharmaceutical composition according to the present invention is influenced by various factors, including the activity of the specific active ingredient used, age, body weight, general health, gender, diet, administration time, administration route, excretion rate, drug formulation, and the severity of the specific disease to be prevented or treated.
  • the dosage of the pharmaceutical composition may vary depending on the patient's condition, body weight, degree of disease, drug form, administration route and period, but may be appropriately selected by a person skilled in the art.
  • the amount that can obtain the maximum effect with the minimum amount without side effects can be administered, more preferably 1 to 10,000 ⁇ g/kg of body weight/day, and even more preferably 10 to 1,000 mg.
  • the effective dose is /kg body weight/day and can be administered repeatedly several times a day. The above dosage does not limit the scope of the present invention in any way.
  • the subject may include an organism, typically a mammal, and preferably a human.
  • the individual may be an individual suffering from or known to have a related disease, symptom, or disorder.
  • the present invention provides a) heavy chain CDR1 represented by the amino acid sequence of SEQ ID NO: 1, heavy chain CDR2 represented by the amino acid sequence of SEQ ID NO: 2, and heavy chain CDR3 represented by the amino acid sequence of SEQ ID NO: 3; and light chain CDR1 represented by the amino acid sequence of SEQ ID NO: 4, light chain CDR2 represented by the amino acid sequence of SEQ ID NO: 5, and light chain CDR3 represented by the amino acid sequence of SEQ ID NO: 6; One compartment containing a humanized anti-VSIG4 antibody or antigen-binding fragment thereof; and b) a two-compartment containing an anti-PD-L1 antibody.
  • the humanized anti-VSIG4 antibody or antigen-binding fragment thereof and anti-PD-L1 antibody included in the kit of the present invention may be administered simultaneously or sequentially depending on the purpose of treatment.
  • the kit may further include a package insert containing instructions for using the humanized anti-VSIG4 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody, and the components may be present in the same container or in separate containers.
  • Suitable containers include, for example, bottles, vials, bags, and syringes.
  • the container may be formed from a variety of materials, such as glass, plastic (e.g., polyvinyl chloride or polyolefin), or metal alloy (e.g., stainless steel or hastelloy).
  • the container holds the formulation and a label on or associated with the container may indicate directions for use.
  • the kit may additionally contain other materials required from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and drug product instructions with instructions for use.
  • the article of manufacture further comprises one or more other agents (e.g., additional chemotherapeutic agents, or anti-neoplastic agents).
  • Suitable containers for one or more agents include, for example, bottles, vials, bags, and syringes.
  • another object of the present invention is a heavy chain CDR1 represented by the amino acid sequence of SEQ ID NO: 1, a heavy chain CDR2 represented by the amino acid sequence of SEQ ID NO: 2, and a heavy chain CDR3 represented by the amino acid sequence of SEQ ID NO: 3; and light chain CDR1 represented by the amino acid sequence of SEQ ID NO: 4, light chain CDR2 represented by the amino acid sequence of SEQ ID NO: 5, and light chain CDR3 represented by the amino acid sequence of SEQ ID NO: 6;
  • an adjuvant anti-cancer treatment for enhancing anti-PD-L1 antibody efficacy comprising a humanized anti-VSIG4 antibody or an antigen-binding fragment thereof.
  • the humanized anti-VSIG4 antibody or antigen-binding fragment thereof can transform the tumor microenvironment into an environment that can increase compliance with immunotherapy, and as a result, the humanized anti-VSIG4 antibody or antigen-binding fragment thereof It was confirmed that simultaneous administration of anti-PD-L1 antibody and anti-PD-L1 antibody can enhance the anticancer effect compared to administration of anti-PD-L1 antibody alone. Therefore, the humanized anti-VSIG4 antibody or binding fragment thereof of the present invention can be used as an auxiliary method to enhance the efficacy of the anti-PD-L1 antibody.
  • the present invention provides a heavy chain CDR1 represented by the amino acid sequence of SEQ ID NO: 1, a heavy chain CDR2 represented by the amino acid sequence of SEQ ID NO: 2, and a heavy chain CDR3 represented by the amino acid sequence of SEQ ID NO: 3; and light chain CDR1 represented by the amino acid sequence of SEQ ID NO: 4, light chain CDR2 represented by the amino acid sequence of SEQ ID NO: 5, and light chain CDR3 represented by the amino acid sequence of SEQ ID NO: 6; It relates to a method for enhancing the efficacy of an anti-PD-L1 antibody, comprising administering to a subject a humanized anti-VSIG4 antibody or antigen-binding fragment thereof.
  • the method can be performed in vivo, in vitro, or ex vivo .
  • the EU103.2 antibody was prepared by humanization from the mouse anti-VSIG4 antibody mu6H8.
  • CDRs were classified using Kabat numbering, and humanized VHs were projected with the corresponding framework and classified as back-mutants of mu6H8 VH CDRs, VH2, VH27, VH30, VH93, and VH94 (hu6H8.3 VH).
  • CDRs were classified using Kabat numbering, and humanized VLs were projected with the corresponding framework and classified as back-mutants of the mu6H8 VL CDRs, VH2, VH4, VH36, and VH46 (hu6H8.3 VL).
  • VHCDR1 VHCDR2 VHCDR3 VLCDR1 VLCDR2 VLCDR3 GISLTT SEQ ID NO: 1 IFWDDNK (SEQ ID NO: 2) VRVYYKNDGYFDV (SEQ ID NO: 3) KSVTTS (SEQ ID NO: 4) LAS (SEQ ID NO: 5) QQSGELPYT (SEQ ID NO: 6)
  • TAMs were isolated from the ascites of an ovarian cancer patient and treated with EU103, and then it was confirmed whether TAMs could be converted into inflammatory macrophages by EU103 treatment and thereby improve the tumor microenvironment.
  • FIG. 1 A schematic diagram of the conversion analysis method performed in the present invention is shown in Figure 1.
  • VSIG4 was confirmed to be expressed in 26.7% of differentiated anti-inflammatory macrophages.
  • Anti-inflammatory macrophages differentiated as above were treated with EU103 of the present invention at various concentrations, and the binding activity of EU103 was confirmed through FACS analysis, and the results are shown in Figure 4.
  • EU103 showed binding activity to VSIG4 of anti-inflammatory macrophages, and showed saturated binding activity at a concentration of 0.3125 ⁇ g/mL or higher.
  • IgG1 antibodies are known to have the disadvantage of showing strong ADCC (Antibody-Dependent Cellular Cytotoxicity) and CDC (Complement-Dependent Cytotoxicity) effects due to their high binding affinity for Fc ⁇ and complement activity, but they have the advantage of structural stability and high flexibility. Therefore, to preserve the antibody's ability to induce the conversion of anti-inflammatory macrophages to inflammatory macrophages by targeting VSIG4, but also to prevent the reaction mediating the elimination of anti-inflammatory macrophages, mutations were added to the Fc region of IgG1. EU103 was prepared in a form in which binding to Fc ⁇ and C1q, the main proteins mediating ADCC and CDC, was removed.
  • ADCC and CDC activities of IgG1, EU103, and EU103-IgG1 were tested using peripheral blood mononuclear cells (PBMC) used in the classical ADCC assay and HeLa cells overexpressing VSIG4 as target cells.
  • PBMC peripheral blood mononuclear cells
  • EU103 introduced three mutations (human IgG1 L234F/L235E/P331S SEQ ID NO: 9) into the IgG1 Fc region to eliminate ADCC and CDC activities, while EU103-IgG1 has wild-type IgG1 Fc.
  • SEQ ID NO: 9 human IgG1 L234F/L235E/P331S (mutation underlined, bold)
  • ADCC activity of EU103 was not observed when compared with EU103-IgG1 introduced with wild-type IgG1 without Fc region mutation.
  • EU103-IgG1 in which no mutation was introduced, cells were killed in a dose-dependent manner.
  • CDC is initiated by the binding of the antibody Fc domain to the complement protein C1q.
  • ELISA was performed to examine EU103 binding to C1q, and the results are shown in Figure 6.
  • EU103 showed minimal binding to C1q protein, which shows that it has a very low level of CDC activity.
  • CFSE staining can measure the number of cell divisions by number of dilutions.
  • CD4+/CD8+ T cells were isolated from peripheral blood mononuclear cells of healthy donors and activated using anti-CD3 antibody.
  • Tumor-associated macrophages do not exist under normal conditions, but are observed in many tumors and are therefore considered important in anticancer treatment.
  • the specific polarization state of tumor-associated macrophages (TAMs), as anti-inflammatory-like macrophages, are important components of the tumor microenvironment and are a subject of important research in anticancer therapy. Converting anti-inflammatory macrophages to a tumor-suppressing inflammatory macrophage phenotype may be a new therapeutic approach for improving anti-tumor immunity.
  • the role of EU103 in tumor-associated macrophages (TAMs) was analyzed to determine whether EU103 can transform TAMs isolated from the ascites of ovarian cancer patients.
  • CD14+ cells were isolated from the ascites of an ovarian cancer patient, and the isolated tumor-associated macrophages (TAM) expressed CD68 and CD163, and at the same time, the expression of VSIG4 was also observed.
  • the isolated tumor-associated macrophages (TAM) were treated with EU103 for 2 days, and changes in the expression of macrophage surface markers and secretion of cytokines and enzymes in the culture medium were measured.
  • LPS/IFN-g was treated as a positive control, and the experimental results are shown in Figure 8.
  • EU103 can improve the tumor microenvironment (TME) by converting tumor-associated macrophages (TAMs) into inflammatory macrophages that suppress tumors, which means that EU103 can exert anticancer effects by improving the tumor microenvironment. It indicates that there is.
  • TEM tumor-associated macrophages
  • EU103 is an antibody that acts on human VSIG4, and its binding affinity for mouse VSIG4 is low and cannot be observed. Therefore, the anticancer effect of EU103 was evaluated using a humanized mouse model introduced with the human immune system.
  • Humanized mice can be simply defined as research mice in which human cells or tissues are transplanted or genes are introduced into immunodeficient mice.
  • To introduce the human immune system the most common methods are transplantation of human hematopoietic stem cells (hu-HSC, CD34+ humanization) or white blood cells present in human peripheral blood (human peripheral blood leukocytes, hu-PBL, PBMC humanization) is separated and injected.
  • orthotopic models are known to be more clinically relevant and better able to predict drug effects.
  • tumor cell lines transfected with the luciferase gene were transplanted and anticancer effects were evaluated through noninvasive visualization of tumor growth, distribution, and metastatic growth through bioluminescence imaging (BLI).
  • BBI bioluminescence imaging
  • tail vein injection was used to engraft the tumor in the lung.
  • differentiated M2 macrophages were injected together with the lung cancer cell line to induce the formation of tumor-related macrophages.
  • Antibody administration was started when the luminescence intensity of the tumor engrafted in the lung was 1 x 10 7 or higher.
  • the test substance was administered a total of 6 times every 3 days. Tumor cells expressing luciferase were visualized using IVIS once a week after tumor cell transplantation and twice a week after antibody administration. After lung orthotopic induction, luciferase density was measured using the IVIS system to confirm lung-specific tumor cell engraftment, but was not observed in other organs.
  • Human IgG (hIgG) was administered as a control group, and the results of tumor size and body weight changes following EU103 administration are shown in Figure 9.
  • Preliminary monkey toxicity studies were performed using liver Kupffer cells (KC) from cynomolgus monkeys.
  • the experimental group included not only Fc-engineered IgG1 but also various isotypes of EU103 such as IgG1 (Anti-VSIG4-IgG1), IgG2 (Anti-VSIG4-euG2), and IgG4 (Anti-VSIG4-IgG4).
  • IgG1 Anti-VSIG4-IgG1
  • IgG2 Anti-VSIG4-euG2
  • IgG4 Anti-VSIG4-IgG4
  • An experiment was conducted targeting . Wild-type IgG1, IgG4, and Fc-engineered IgG1 EU103 at a concentration of 20 mg/kg were injected into monkeys and the effect on liver Kupffer cells was evaluated. The results are shown in Figure 10.
  • Kupffer cells Preserving Kupffer cells is important for immune homeostasis. Because Kupffer cells express VSIG4, a depletion effect by the ADCC activity of EU103-IgG1 (Anti-VSIG4-IgG1) was expected. Kupffer cells were isolated from the liver of cynomolgus monkeys to analyze depletion of Kupffer cells using FACS. As shown in Figure 10, the test results confirmed that Kupffer cells constitutively express both CD4 and VSIG4. EU103-IgG1 (Anti-VSIG4-IgG1) of IgG1 wild type reduced Kupffer cells by 64%, but EU103 of the present invention had no significant effect on the Kupffer cell population of cynomolgus monkeys. Additionally, no changes in clinical chemistry, including normal ALT and AST, were observed in monkeys administered EU103. In other words, no drug-related adverse reactions were observed in monkeys administered EU103, and clinical signs were normal at 20 mg/kg.
  • Tecentriq (atezolizumab) was used as the anti-PD-L1 antibody.
  • EU103 or Tecentriq alone administration group a dose of 8 mg/kg was administered, and in the combination administration group, EU103 5 mg/kg and Tecentriq 3 mg/kg were administered, and the results are shown in Figure 12 and Table 4.
  • TGI TV (%) [(V i -T i )/V i ]*100
  • T i treated group at endpoint day
  • V i hIgG group at endpoint day
  • the size of the tumor was significantly reduced in the single-administration group and the combined administration group compared to the control group (A, B).
  • the group treated with the combination of EU103 and Tecentriq showed superior antitumor activity than the group treated with EU103 or Tecentriq alone from day 26 onwards.
  • Tumor growth inhibition data was analyzed on day 43, the end date of the test, and the results are shown in Figure 12C.
  • tumor growth inhibition (TGITV (%)) in the EU103 and Tecentriq groups was 80.14% and 72.29%, respectively, and the combination group (Combo) showed an inhibition rate of 94.11%.
  • Monotherapy with EU103 or Tecentriq reduced tumor growth up to 43 days after tumor injection.
  • the combination therapy of EU103 and Tecentriq showed a clear synergistic anti-tumor effect in a humanized orthotopic lung cancer model.
  • the response of the anti-tumor effect of this combination was very immediate upon drug injection.
  • EU103 can efficiently inhibit tumor growth and significantly increase the anti-tumor effect in combination therapy with Tecentriq, an anti-PD-L1 antibody.

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Abstract

La présente invention concerne une composition pour la prévention ou le traitement du cancer comprenant un anticorps anti-VISG4 humanisé ou un fragment de liaison à l'antigène de celui-ci, et une composition comprenant en outre un anticorps anti-PD-L1 qui présente un effet significatif de prévention ou de traitement du cancer. L'anticorps anti-VISG4 humanisé ou le fragment de liaison de celui-ci selon la présente invention peut présenter un effet anticancéreux par régulation des cellules immunitaires dans le corps et améliorer le micro-environnement du tissu cancéreux, et lorsqu'il est administré en combinaison avec un anticorps anti-PD-L1, peut présenter un effet anticancéreux significatif. Par conséquent, la présente invention peut être utilisée dans divers domaines de prévention ou de traitement du cancer, en particulier dans la prévention ou le traitement de types de cancer qui ont un mauvais pronostic par rapport à une thérapie par inhibiteur de point de contrôle immunitaire.
PCT/KR2023/016397 2022-10-21 2023-10-20 Composition anticancéreuse comprenant un anticorps anti-vsig4 WO2024085726A1 (fr)

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Citations (3)

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KR20210087028A (ko) * 2018-09-28 2021-07-09 주식회사 유틸렉스 항-인간 vsig4 항체 및 이의 용도
WO2021243169A1 (fr) * 2020-05-29 2021-12-02 Verseau Therapeutics, Inc. Compositions anti-vsig4 et procédés de modulation des phénotypes inflammatoires des cellules myéloïdes et leurs utilisations
KR20220088847A (ko) * 2019-09-04 2022-06-28 주식회사 와이바이오로직스 항-vsig4 항체 또는 항원-결합 단편 및 이들의 용도

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KR20210087028A (ko) * 2018-09-28 2021-07-09 주식회사 유틸렉스 항-인간 vsig4 항체 및 이의 용도
KR20220088847A (ko) * 2019-09-04 2022-06-28 주식회사 와이바이오로직스 항-vsig4 항체 또는 항원-결합 단편 및 이들의 용도
WO2021243169A1 (fr) * 2020-05-29 2021-12-02 Verseau Therapeutics, Inc. Compositions anti-vsig4 et procédés de modulation des phénotypes inflammatoires des cellules myéloïdes et leurs utilisations

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