WO2021213434A1 - 一种抗Nectin-4的抗体及其应用 - Google Patents

一种抗Nectin-4的抗体及其应用 Download PDF

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WO2021213434A1
WO2021213434A1 PCT/CN2021/088661 CN2021088661W WO2021213434A1 WO 2021213434 A1 WO2021213434 A1 WO 2021213434A1 CN 2021088661 W CN2021088661 W CN 2021088661W WO 2021213434 A1 WO2021213434 A1 WO 2021213434A1
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cdr
amino acid
acid sequence
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sequence shown
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French (fr)
Chinese (zh)
Inventor
任红媛
朱戬
林鉴
王骊淳
徐晓红
邓小芳
毕建军
王晋
吴建
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Mabwell Shanghai Bioscience Co Ltd
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Mabwell Shanghai Bioscience Co Ltd
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Priority to BR112022021322A priority Critical patent/BR112022021322A2/pt
Priority to AU2021260639A priority patent/AU2021260639A1/en
Priority to MX2022013163A priority patent/MX2022013163A/es
Priority to KR1020227040582A priority patent/KR20230007406A/ko
Priority to US17/996,403 priority patent/US12590150B2/en
Priority to EP21791797.0A priority patent/EP4141029A4/en
Priority to JP2022563917A priority patent/JP7813721B2/ja
Priority to CN202180030277.7A priority patent/CN115427452B/zh
Priority to CA3176385A priority patent/CA3176385A1/en
Publication of WO2021213434A1 publication Critical patent/WO2021213434A1/zh
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    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], 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
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    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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Definitions

  • the present invention belongs to the field of antibody medicines. Specifically, the present invention relates to antibodies against human Nectin-4 and their use for preparing medicines.
  • Nectin-4 (also known as PVRL4, poliovirus receptor-like molecule 4) is a 66KD transmembrane glycoprotein, which belongs to the IG superfamily protein molecule of the Nectin family. Its extracellular domain consists of three Ig It is composed of VCC-like domain (VCC type) and participates in the formation and maintenance of adhesion junctions together with cadherin.
  • VCC VCC-like domain
  • Nectin-4 is closely related to the occurrence and development of a variety of tumor cells. It has been found that Nectin-4 is expressed in a variety of solid tumors, especially bladder cancer; in breast cancer, ovarian cancer and lung cancer, as a tumor-associated antigen, it accounts for 50% of breast cancer, 49% of ovarian cancer and 86% of lung cancer. The tissue expression detection rate of these epithelial malignancies, and plays a key role in the occurrence, invasion and metastasis of these epithelial malignant tumors. Therefore, Nectin-4 has become an important target for the diagnosis and treatment of many solid tumors.
  • the main drug for Nectin-4 is Enfortumab vedotin, which is an antibody-conjugated drug, which is a combination of a monoclonal antibody against Nectin-4 and a cell-killing drug monomethyl auristatin E (MMAE). It is used to treat bladder cancer, especially It is urothelial cancer, which has been approved by the FDA as a breakthrough therapy in March 2018.
  • adhesion factor Nnectin-4 can be used not only as an effective prognostic factor for breast cancer, but also as an effective therapeutic target for patients with triple-negative breast cancer (TNBC); in vivo and in vitro studies have confirmed that antibodies against Nectin-4 Conjugated drugs (ADC) have a good effect on local and metastatic TNBC.
  • ADC Nectin-4 Conjugated drugs
  • the technical problem to be solved by the present invention is to obtain a high-affinity antibody that specifically binds to Nectin-4 through hybridoma screening and humanization technology, wherein a fully human antibody sequence is obtained through humanization modification.
  • the purpose of the present invention is to provide an antibody molecule or fragment thereof that specifically binds to Nectin-4, especially human Nectin-4, and to provide its use.
  • the fragments of the antibody molecule of the present invention cover various functional fragments of antibodies, for example, antigen-binding parts thereof, such as Fab, F(ab') 2 or scFv fragments.
  • the present invention provides an antibody molecule or a fragment thereof, the antibody molecule or a fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), the heavy chain variable region and the light chain
  • VH heavy chain variable region
  • VL light chain variable region
  • the variable regions respectively comprise a combination of heavy chain CDRs and light chain CDRs selected from:
  • CDR-H1 GYTFTTY
  • CDR-H2 YPGNVN
  • CDR-H3 GLYYFDY
  • SEQ ID NO: 35, 39, 43 in sequence and, shown in SEQ ID NO: 45, 47, 49 of CDR-L1 (KASQSVSNDVA), CDR-L2 (YASNRYT), CDR-L3 (QQDYSSPYT);
  • CDR-H1 GYTFTTYYIH
  • CDR-H2 WIYPGNVNTK
  • CDR-H3 GLYYFDY
  • SEQ ID NO: 36, 40, 43 in sequence and, shown in SEQ ID NO: 45, 47, 49 of CDR-L1 (KASQSVSNDVA), CDR-L2 (YASNRYT), CDR-L3 (QQDYSSPYT);
  • CDR-H1 (TYYIH), CDR-H2 (WIYPGNVNTKYNEKFKG), CDR-H3 (GLYYFDY) shown in SEQ ID NO: 37, 41, 43 in sequence; and, shown in SEQ ID NO: 45, 47, 49 of CDR-L1 (KASQSVSNDVA), CDR-L2 (YASNRYT), CDR-L3 (QQDYSSPYT);
  • CDR-H1 TTYYIH
  • CDR-H2 WIGWIYPGNVNTK
  • CDR-H3 ARGLYYFD
  • SEQ ID NO: 38, 42, 44 SEQ ID NO: 44
  • SEQ ID NO: 46, 48, 50 CDR-L1 (SNDVAWY), CDR-L2 (LLIYYASNRY), CDR-L3 (QQDYSSPY);
  • CDR-H1 (GFSLIDY), CDR-H2 (WGDGK), CDR-H3 (QGGLLFYAMDY) shown in SEQ ID NO: 51, 55, 59 in sequence; and, shown in SEQ ID NO: 61, 63, 65 CDR-L1 (KSSQSLLNSYSQKNYLA), CDR-L2 (FASTRES), CDR-L3 (QQHYNTPFT);
  • CDR-H1 (GFSLIDYGVS), CDR-H2 (VIWGDGKIY), CDR-H3 (QGGLLFYAMDY) shown in SEQ ID NO: 52, 56, 59; and, shown in SEQ ID NO: 61, 63, 65 CDR-L1 (KSSQSLLNSYSQKNYLA), CDR-L2 (FASTRES), CDR-L3 (QQHYNTPFT);
  • CDR-H1 (DYGVS), CDR-H2 (VIWGDGKIYYNSVLKS), CDR-H3 (QGGLLFYAMDY) shown in SEQ ID NO: 53, 57, 59 in sequence; and, shown in SEQ ID NO: 61, 63, 65 CDR-L1 (KSSQSLLNSYSQKNYLA), CDR-L2 (FASTRES), CDR-L3 (QQHYNTPFT);
  • CDR-H1 IDYGVS
  • CDR-H2 word GVIWGDGKIY
  • CDR-H3 AKQGGLLFYAMD
  • SEQ ID NO: 54, 58, 60 shown in SEQ ID NO: 54, 58, 60; and, shown in SEQ ID NO: 62, 64, 66 CDR-L1 (LNSYSQKNYLAWY), CDR-L2 (LLIYFASTRE), CDR-L3 (QQHYNTPF);
  • CDR-H1 (GFSLIDY), CDR-H2 (WGDGK), CDR-H3 (QGGLLFYAMDY) shown in SEQ ID NO: 51, 55, 59; and, shown in SEQ ID NO: 67, 63, 65 CDR-L1 (KSSQSLLNTYSQKNYLA), CDR-L2 (FASTRES), CDR-L3 (QQHYNTPFT);
  • CDR-H1 (GFSLIDY), CDR-H2 (WGDAK), CDR-H3 (QGGLLFYAMDY) shown in SEQ ID NO: 51, 68, 59; and, shown in SEQ ID NO: 67, 63, 65 CDR-L1 (KSSQSLLNTYSQKNYLA), CDR-L2 (FASTRES), CDR-L3 (QQHYNTPFT);
  • CDR-H1 (GFSLIDY), CDR-H2 (WGGGK), CDR-H3 (QGGLLFYAMDY) shown in SEQ ID NO: 51, 69, 59; and, shown in SEQ ID NO: 67, 63, 65 CDR-L1 (KSSQSLLNTYSQKNYLA), CDR-L2 (FASTRES), CDR-L3 (QQHYNTPFT);
  • CDR-H1 GYTFTSY
  • CDR-H2 YPGNAN
  • CDR-H3 SVYYFDY
  • SEQ ID NO: 70, 74, 78 shown in SEQ ID NO: 45, 80, 49 of CDR-L1 (KASQSVSNDVA), CDR-L2 (YASNRNT), CDR-L3 (QQDYSSPYT);
  • CDR-H1 GYTFTSYYIH
  • CDR-H2 WIYPGNANNK
  • CDR-H3 SVYYFDY
  • SEQ ID NO: 71, 75, 78 in sequence and, shown in SEQ ID NO: 45, 80, 49 of CDR-L1 (KASQSVSNDVA), CDR-L2 (YASNRNT), CDR-L3 (QQDYSSPYT);
  • CDR-H1 SYYIH
  • CDR-H2 WIYPGNANNKYNENFKG
  • CDR-H3 SVYYFDY
  • SEQ ID NO: 72, 76, 78 in sequence; and, shown in SEQ ID NO: 45, 80, 49 of CDR-L1 (KASQSVSNDVA), CDR-L2 (YASNRNT), CDR-L3 (QQDYSSPYT);
  • CDR-H1 (TSYYIH), CDR-H2 (WIGWIYPGNANNK), CDR-H3 (ARSVYYFD) shown in SEQ ID NO: 73, 77, 79 in sequence; and, shown in SEQ ID NO: 46, 81, 50 CDR-L1 (SNDVAWY), CDR-L2 (LLIYYASNRN), CDR-L3 (QQDYSSPY);
  • CDR-H1 GYSFTDY
  • CDR-H2 NPNNGN
  • CDR-H3 EDRYAFAY
  • SEQ ID NO: 82, 86, 90 shown in SEQ ID NO: 82, 86, 90; and, shown in SEQ ID NO: 92, 94, 96 CDR-L1 (RASQSVSTSSYTYMH), CDR-L2 (YASNLES), CDR-L3 (QHTWEIPYT);
  • CDR-H1 GYSFTDYYMH
  • CDR-H2 RVNPNNGNTL
  • CDR-H3 EDRYAFAY
  • SEQ ID NO: 83, 87, 90 SEQ ID NO: 83, 87, 90
  • SEQ ID NO: 92, 94, 96 CDR-L1 RASQSVSTSSYTYMH
  • CDR-L2 YASNLES
  • CDR-L3 QHTWEIPYT
  • CDR-H1 (DYYMH), CDR-H2 (RVNPNNGNTLYNQKFRG), CDR-H3 (EDRYAFAY) shown in SEQ ID NO: 84, 88, 90; and, shown in SEQ ID NO: 92, 94, 96 CDR-L1 (RASQSVSTSSYTYMH), CDR-L2 (YASNLES), CDR-L3 (QHTWEIPYT);
  • CDR-H1 (TDYYMH), CDR-H2 (WIGRVNPNNGNTL), CDR-H3 (AREDRYAFA) shown in SEQ ID NO: 85, 89, 91 in sequence; and, shown in SEQ ID NO: 93, 95, 97 CDR-L1 (STSSYTYMHWY), CDR-L2 (LLIKYASNLE), CDR-L3 (QHTWEIPY).
  • the heavy chain variable region or the light chain variable region in the antibody molecule or fragment thereof of the present invention is divided into FR1-CDR1-FR2-
  • the sequence of CDR2-FR3-CDR3-FR4 includes the above-mentioned domain components, where FR is the framework region.
  • the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO: 7, 9 or 10 or has at least 75% identity with the amino acid sequence.
  • An amino acid sequence; and, the light chain variable region comprises the amino acid sequence shown in SEQ ID NO: 8, 11 or 12 or an amino acid sequence having at least 75% identity with the amino acid sequence; or,
  • the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO: 13, 15, 16, 18, 19, 20, or 21 or an amino acid sequence having at least 75% identity with the amino acid sequence; and, the The light chain variable region comprises the amino acid sequence shown in SEQ ID NO: 14, 22, 23 or 25 or an amino acid sequence having at least 75% identity with the amino acid sequence; or
  • the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO: 27, 29 or 30 or an amino acid sequence having at least 75% identity with the amino acid sequence; and, the light chain variable region comprises the amino acid sequence shown in The amino acid sequence of SEQ ID NO: 28, 31 or 32 or an amino acid sequence having at least 75% identity with the amino acid sequence; or,
  • the heavy chain variable region includes the amino acid sequence shown in SEQ ID NO: 33 or an amino acid sequence having at least 75% identity with the amino acid sequence; and, the light chain variable region includes the amino acid sequence shown in SEQ ID NO: The amino acid sequence of 34 or an amino acid sequence having at least 75% identity with the amino acid sequence.
  • variable region of the heavy chain and the variable region of the light chain in the antibody molecule or a fragment thereof are selected from a combination of the following amino acid sequences:
  • amino acid sequence shown in SEQ ID NO: 7 or the amino acid sequence having at least 75% identity with the amino acid sequence shown in SEQ ID NO: 7; and, the amino acid sequence shown in SEQ ID NO: 8 Or an amino acid sequence having at least 75% identity with the amino acid sequence shown in SEQ ID NO: 8;
  • amino acid sequence shown in SEQ ID NO: 9 or the amino acid sequence having at least 75% identity with the amino acid sequence shown in SEQ ID NO: 9; and, the amino acid sequence shown in SEQ ID NO: 12 Or an amino acid sequence having at least 75% identity with the amino acid sequence shown in SEQ ID NO: 12;
  • amino acid sequence shown in SEQ ID NO: 10 or the amino acid sequence having at least 75% identity with the amino acid sequence shown in SEQ ID NO: 10; and, the amino acid sequence shown in SEQ ID NO: 12 Or an amino acid sequence having at least 75% identity with the amino acid sequence shown in SEQ ID NO: 12;
  • amino acid sequence shown in SEQ ID NO: 33 or the amino acid sequence having at least 75% identity with the amino acid sequence shown in SEQ ID NO: 33; and, the amino acid sequence shown in SEQ ID NO: 34 Or an amino acid sequence having at least 75% identity with the amino acid sequence shown in SEQ ID NO: 34.
  • the antibody molecule or fragment thereof provided by the present invention binds to poliovirus receptor-like molecule 4 (Nectin-4), preferably mammalian Nectin-4, more preferably primate Nectin-4, further preferably human or monkey Nectin -4, especially human Nectin-4.
  • Nectin-4 poliovirus receptor-like molecule 4
  • mammalian Nectin-4 more preferably primate Nectin-4, further preferably human or monkey Nectin -4, especially human Nectin-4.
  • the antibody molecule is a murine antibody, a chimeric antibody or a fully or partially humanized antibody; the fragment is any fragment of the antibody molecule that can specifically bind to Nectin-4, such as scFv, dsFv, ( dsFv) 2 , Fab, Fab', F(ab') 2 or Fv fragment.
  • Nectin-4 such as scFv, dsFv, ( dsFv) 2 , Fab, Fab', F(ab') 2 or Fv fragment.
  • the antibody molecule is a monoclonal antibody or a single chain antibody.
  • the antibody molecule or fragment thereof further comprises a human or murine constant region, preferably a murine or human heavy chain constant region (CH) and/or a light chain constant region (CL); preferably, the antibody molecule Or fragments thereof include a heavy chain and a light chain, for example, two heavy chains and a light chain. More preferably, the antibody molecule or a fragment thereof comprises a heavy chain constant region of IgG, IgA, IgM, IgD or IgE and/or a kappa or lambda light chain constant region.
  • the antibody molecule provided by the present invention is a monoclonal antibody, preferably a humanized monoclonal antibody; preferably, the heavy chain constant region of the monoclonal antibody is of type IgG1, and the light chain constant region is ⁇ type.
  • the heavy chain constant region of the monoclonal antibody comprises the amino acid sequence shown in SEQ ID NO: 4 or an amino acid sequence having at least 75% identity with the amino acid sequence;
  • the light chain constant region of the monoclonal antibody comprises The amino acid sequence shown in SEQ ID NO: 5 or an amino acid sequence having at least 75% identity with the amino acid sequence.
  • At least 75% identity is the identity of any percentage number between 75% and 100%, such as 75%, 80%, 85%, 90%, or even 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity.
  • the present invention provides a nucleic acid molecule comprising a nucleotide sequence encoding a light chain variable region, a heavy chain variable region, a heavy chain, or a light chain contained in the antibody molecule of the present invention or a fragment thereof .
  • the nucleic acid molecule of the present invention can be cloned into a vector, and then transformed or transfected into a host cell. Therefore, in yet another aspect, the present invention provides a vector comprising the nucleic acid molecule of the present invention.
  • the vector can be a eukaryotic expression vector, a prokaryotic expression vector, an artificial chromosome, a phage vector, and the like.
  • the vector or nucleic acid molecule of the present invention can be used to transform or transfect a host cell or enter the host cell in any manner for the purpose of preservation or expression of antibodies. Therefore, in another aspect, the present invention provides a host cell, which contains the nucleic acid molecule and/or vector of the present invention, or the host cell is transformed or transfected by the nucleic acid molecule and/or vector of the present invention.
  • the host cell can be any prokaryotic or eukaryotic cell, such as a bacterial or insect, fungal, plant or animal cell.
  • the antibody molecule provided by the present invention can be obtained by any method known in the art.
  • the heavy chain variable region and/or light chain variable region of the antibody can be obtained first from the nucleic acid molecule provided by the present invention, or the heavy chain and/or light chain of the antibody molecule can be obtained, and then combined with the antibody molecule
  • the optional other domains of the antibody are assembled into antibodies; or, in the host cell provided by the present invention, the heavy chain variable region and/or light chain variable region of the antibody molecule or the heavy chain and/or heavy chain of the antibody molecule are expressed in the host cell provided by the present invention.
  • the host cell is cultured.
  • the method further includes the step of recovering the antibody molecules produced.
  • the antibody molecules or fragments thereof, nucleic acid molecules, vectors, host cells, or fusion proteins provided by the present invention can be included in a composition, more particularly in a pharmaceutical preparation, so as to be used for various purposes according to actual needs. Therefore, in another aspect, the present invention also provides a composition comprising the antibody molecules or fragments thereof, nucleic acid molecules, vectors and/or host cells provided by the present invention.
  • the composition is a pharmaceutical composition, which optionally further comprises a pharmaceutically acceptable carrier, adjuvant or excipient.
  • the present invention also provides the use of the antibody molecule or fragments thereof, nucleic acid molecules, vectors, host cells and/or compositions in the preparation of reagents for detecting or diagnosing diseases or disorders. .
  • the present invention also provides a method for detecting or diagnosing a disease or disorder, which method comprises combining the antibody molecule or fragment, nucleic acid molecule, vector, host cell and/or composition of the present invention with a subject Contact with the sample of the person.
  • the subject is a mammal, preferably a primate, and more preferably a human.
  • the present invention also provides the use of the antibody molecule or fragments thereof in the preparation of antibody drug conjugates.
  • the present invention provides an antibody drug conjugate, which is formed by coupling the antibody molecule of the present invention or a fragment thereof with a cytotoxic moiety.
  • the cytotoxic part is a tubulin inhibitor, a topoisomerase inhibitor or a DNA binding agent.
  • the tubulin inhibitor is selected from maytansine derivatives, Monomethylauristatin E (MMAE), Monomethylauristatin F (MMAF), Monomethyl Dolastatin 10, Tubulysin derivatives, Cryptophycin derivatives and Taltobulin.
  • the topoisomerase inhibitor is selected from the PNU-159682 derivative of doxorubicin metabolite and the SN38 derivative of irinotecan (CPT-11) metabolite.
  • the DNA binding agent is selected from PBD derivatives and Duocarmycin derivatives.
  • the present invention also provides the use of the antibody molecule or fragments thereof, nucleic acid molecules, vectors, host cells, compositions and/or antibody drug conjugates in the preparation of drugs for preventing or treating diseases or disorders.
  • the present invention also provides a method for preventing or treating a disease or disorder, the method comprising administering the antibody molecule or fragment, nucleic acid molecule, vector, host cell, or combination of the present invention to a subject in need thereof And/or antibody-drug conjugates.
  • the subject is a mammal, more preferably a human.
  • the present invention provides a kit comprising the antibody molecule or fragments thereof, nucleic acid molecules, vectors, host cells, compositions and/or antibody drug conjugates of the present invention.
  • the kit can be used for treatment, detection or diagnosis purposes, such as treatment, detection or diagnosis of diseases or disorders.
  • the antibody molecule or its fragments, nucleic acid molecules, vectors, host cells, compositions and/or antibody drug conjugates can be used to treat diseases or disorders related to the high expression of Nectin-4.
  • the disease or disorder is a tumor or cancer with high expression of Nectin-4, especially a solid tumor.
  • the disease or disorder is bladder cancer, pancreatic cancer, breast cancer (including triple-negative subtypes and basal subtypes), non-small cell lung cancer, gastric cancer, esophageal cancer, ovarian cancer, etc.; especially bladder cancer, breast cancer, Ovarian cancer or lung cancer.
  • the present invention obtains a high-affinity antibody that specifically binds to Nectin-4 through hybridoma screening and humanization technology, wherein a fully human antibody sequence is obtained through humanization modification.
  • a fully human antibody sequence is obtained through humanization modification.
  • an effective clinical lead drug molecule sequence was obtained.
  • Figure 1 shows the results of flow cytometry identification of antigen-expressing cell lines, in which small figure 1A: HT-1376 bladder cancer cells, and small figure 1B: CHO-huNectin4S8 cells.
  • Figure 2 shows the results of the FACS binding activity assay of the culture supernatant of hybridoma cells, in which small figure 2A: the first round of screening, and small figure 2B: the second round of screening.
  • Figure 3 shows the results of the FACS binding experiment of the antibody and the cells expressing BT474.
  • Figure 4 shows the results of the endocytosis activity of the antibody in BT474 cells.
  • Figure 5 shows the results of FACS binding experiments between antibodies and different cells expressing huNectin4, muNectin4, and cynoNectin4.
  • Figure 6 shows the results of the binding experiment between antibodies and members of the Nectin protein family, in which panel 6A: Nectin-1, panel 6B: Nectin-2, panel 6C: Nectin-3, panel 6D: Nectin-4.
  • Figure 7 shows the results of the antibody's monkey serum stability test, in which small figure 7A: control antibody Enfortumab, small figure 7B: 42D20 hz10.
  • Figure 8 shows the metabolism of antibodies in mice, in which small figure 8A: control antibody Enfortumab, small figure 8B: 42D20 hz10.
  • the heavy chain amino acid sequence of the control antibody Enfortumab is shown in SEQ ID NO: 1, and the light chain amino acid sequence is shown in SEQ ID NO: 2.
  • the antibody sequences of the present invention are shown in Table I to Table IV.
  • Antigen NECTIN4 recombinant protein (serial number: NP_002178.2, 32aa-349aa), shown in SEQ ID NO: 3.
  • Enfortumab antibody light chain variable region and heavy chain variable region genes were cloned into the eukaryotic expression vector pCDNA3.1 upstream of the human-kappa light chain constant region and human IgG1 heavy chain constant region coding genes, respectively, to obtain Enfortumab light and heavy chain expression plasmids were transformed into E. coli for amplification, and a large number of plasmids containing Enfortumab antibody light chain (SEQ ID NO: 2) and heavy chain (SEQ ID NO: 1) were isolated and obtained. Amine (PEI) was mixed and co-transfected into HEK293 cells. The cells were transfected for 5-6 days, the culture supernatant was taken, and the expression supernatant was purified by Mabselect affinity chromatography column to obtain Enfortumab antibody.
  • PKI Protein
  • Nectin-4 gene was cloned from the vector containing Nectin-4 cDNA (Beijing Yiqiao Shenzhou, Cat: HG19771-UT) by PCR, and the reading frame of Nectin-4 gene was digested by restriction enzyme method It was cloned into a stable expression vector containing glutamine synthetase (GS) screening gene, electrotransfected (Nucleofector IIb, Lonza) suspension cultured CHO-K1 cells, and the transfected cells were placed in a 50 ⁇ M MSX (Sigma , Cat: M5379) CD CHO AGTTM medium (Gibco, Cat: 12490-025), seeded in 96-well cell culture plate, 37°C, 5% CO 2 static culture for 2-3 weeks, screening by MSX pressure , Obtain 9 cell growth holes from pre-screening under the microscope, and expand them to 24-well cell culture plates. Finally, the high-expressing antigen clone S8 is selected by flow
  • the high-expressing clone S8 was named CHO-huNectin4 S8.
  • the comparison and identification results of this cell and the endogenously expressing Nectin-4 HT-1376 bladder cancer cells are shown in Figure 1.
  • mice Ten 8-week-old Balb/c mice were divided into two groups, using two methods of traditional immunization and rapid immunization respectively.
  • the CHO-huNectin4 S8 engineered cell line for traditional immunization was used as the immunizing agent, and the recombinant protein human Nectin4 (purchased from Nearshore protein, Cat: CJ19) is an immunizing agent.
  • mice Blood was collected from mice before immunization as a negative control.
  • the two immunizing agents were injected intraperitoneally, and the second and third immunizations were performed at 2 weeks intervals. Blood was collected one week after the third immunization to measure the titer.
  • the mice with high titer were selected for sprint immunization 3 days before the fusion.
  • mice The spleen and lymph nodes of the mice were aseptically taken, ground to prepare a cell suspension, filtered by a cell filter, and then red blood cells were lysed, combined and counted after lysis. Mix the B cells and SP20 myeloma cells at a ratio of 1:2. After centrifugation, wash the mixed cells twice with electrofusion solution, then resuspend the cells and adjust the density to about 1-2 ⁇ 10 7 /ml. Add the cell suspension to the electric shock cup for fusion.
  • the culture supernatant of hybridoma cells was taken for analysis by FACS, and the positive wells that could bind to CHO-huNECTIN4S8 cells stably expressing human Nectin4 antigen on the cell surface were screened and did not bind to blank CHOK1 cells.
  • the screened positive wells are single-celled by the limiting dilution method, and the subcloning is terminated when the positive results of the two consecutive subclones are 100%, and the obtained hybridoma cell line secretes only one antibody.
  • the obtained murine monoclonal antibody is named after the hybridoma cell line ID.
  • the total RNA of the cells is extracted according to the instructions of the RNAfast200 kit (Shanghai Feijie Biotechnology Co., Ltd.); the hybridoma cells are extracted using 5 ⁇ PrimeScript RT Master Mix (Takara) Reverse transcription of total RNA into cDNA; use degenerate primers (Anke Krebber.
  • the heavy chain variable region sequence of the murine anti-human Nectin-4 monoclonal antibody and the publicly published heavy chain constant region sequence of the human monoclonal antibody IgG1 subclass (SEQ ID NO: 4) were spliced together to construct a mammal In the cell expression vector; the light chain variable region sequence of the murine anti-human Nectin-4 monoclonal antibody and the publicly published light chain constant region sequence of the human monoclonal antibody ⁇ subclass (SEQ ID NO: 5) are spliced together , Constructed into mammalian cell expression vectors.
  • the constructed anti-human Nectin-4 chimeric antibody heavy chain vector and light chain vector were paired and mixed, and HEK293 cells were transfected with PEI. The cell supernatant was collected about 7 days later, and the anti-human NECTIN4 chimeric antibody protein was purified by Mabselect.
  • murine antibody named xiIgG.
  • the humanized antibody is named "mouse antibody named hzmn", where m and n are the numbers of the humanized (hz) modified sequences (VH_hz and VL_hz) of the murine antibody VH and VL, respectively.
  • the ADC corresponding to the antibody is named as "antibody designation-E”.
  • the anti-human Nectin-4 control antibody Enfortumumab, the antibody of the present invention, or the ADC is diluted with a 2-fold gradient from the starting concentration of 100 nM to a total of 16 concentration points, and 10 ul of the antibody at each concentration point is added to a 384-well plate.
  • BT474 cells (breast cancer cells) expressing Nectin-4 on the cell surface by centrifugation at 100g room temperature for 5 minutes. Wash the cells once with PBS containing 0.5% BSA, centrifuge at 100g room temperature for 5 minutes, and resuspend the cells to a density of about 2x10 6 cells/ml , Take 10ul and add it to the wells of the 384-well plate that has been added with antibody. After incubating for 1 hour at 4°C, a fluorescently-labeled goat anti-human IgG secondary antibody was added. After continuing to incubate at 4°C for 1 hour, the average fluorescence reading of the cell population was analyzed by flow cytometry.
  • HEK293 cells expressing murine Nectin4 (NP_082169): HEK-muNectin4;
  • HEK293 cells expressing CynoNectin4 (SEQ ID NO: 6): HEK-cynoNectin4.
  • the His-tagged human NECTIN4 antigen is coupled to both the sensor chip CAP analysis channel and the control sample channel, and then the serially diluted antibody sample is passed through the analysis channel and the control sample channel (starting The concentration was 20 nM, and 8 concentration points were diluted 1:3, and the concentration point was set at 0.741 nm to repeat), and the light response value after the antibody antigen binding was measured. After instrument software fitting analysis (1:1 binding mode), the binding constant Kon, dissociation constant Koff, and affinity constant KD of the antibody are finally obtained.
  • Antibody (primary antibody): the antibody of the present invention.
  • CD111/Nectin-1/PVRL1 Antibody Rabbit Fab, 80244-RP01-100, Sinobiologics.
  • Anti-Nectin 2 antibody(ab233085) Rabbit antibody, Abcam.
  • Anti-Nectin 3 antibody (ab137961), Rabbit antibody, Abcam.
  • the antibody of the present invention and the control antibody have the same properties, can specifically recognize Nectin-4 antigen, have a dose-dependent binding effect, and do not have cross-binding activity with other proteins of the same family of Nectin-4. .
  • test antibody FBS
  • test antibody binding antigen anti-huIgG Fab monoclonal antibody
  • anti-huIgG Fab monoclonal antibody Sigma, I5260-1ML
  • HRP-labeled goat anti-human IgG secondary antibody Jackson, code: 109-035-098.
  • the result proves that after the antibody of the present invention is incubated at 37°C for 21 days, there is no change in the effective antibody content, that is, it can stably exist at 37°C for more than 21 days.
  • mice Female Balb/C mice, 3 mice/group, respectively in the tail vein or abdominal cavity, 200ug/mouse;
  • the antibody diluent dilutes the antibody standard, and the dilution of the standard is still adjusted according to the preliminary experiment, so that the standard can be fitted to a linear curve (if appropriate software is available, an S-shaped curve can also be fitted).
  • the lower limit of detection is 9.77ng/ml.

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PCT/CN2021/088661 2020-04-21 2021-04-21 一种抗Nectin-4的抗体及其应用 Ceased WO2021213434A1 (zh)

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BR112022021322A BR112022021322A2 (pt) 2020-04-21 2021-04-21 Anticorpo contra nectina-4 e aplicação do mesmo
AU2021260639A AU2021260639A1 (en) 2020-04-21 2021-04-21 Antibody against Nectin-4 and application thereof
MX2022013163A MX2022013163A (es) 2020-04-21 2021-04-21 Anticuerpo contra nectin-4 y aplicacion del mismo.
KR1020227040582A KR20230007406A (ko) 2020-04-21 2021-04-21 넥틴-4 (nectin-4) 에 대한 항체 및 이의 응용
US17/996,403 US12590150B2 (en) 2020-04-21 2021-04-21 Antibody against Nectin-4 and application thereof
EP21791797.0A EP4141029A4 (en) 2020-04-21 2021-04-21 ANTIBODIES AGAINST NECTIN-4 AND ITS APPLICATION
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US12594343B2 (en) 2020-01-31 2026-04-07 Innate Pharma Treatment of cancer
WO2022112356A1 (en) * 2020-11-25 2022-06-02 Innate Pharma Treatment of cancer
CN116478279A (zh) * 2021-12-31 2023-07-25 武汉瑞法医疗器械有限公司 乙型肝炎病毒表面抗原纳米抗体吸附剂及制备方法和应用
WO2023221971A1 (zh) * 2022-05-16 2023-11-23 江苏恒瑞医药股份有限公司 一种含抗Nectin-4抗体药物偶联物的药物组合物及其用途
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EP4324849A1 (en) * 2022-08-18 2024-02-21 Emergence Therapeutics AG Humanized anti-nectin-4 antibodies
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