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WO1992020799A1 - Sequence d'acides amines d'anticorps monoclonal humain anticancer et sequence de bases d'adn codant pour ces acides amines - Google Patents

Sequence d'acides amines d'anticorps monoclonal humain anticancer et sequence de bases d'adn codant pour ces acides amines Download PDF

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Publication number
WO1992020799A1
WO1992020799A1 PCT/JP1992/000650 JP9200650W WO9220799A1 WO 1992020799 A1 WO1992020799 A1 WO 1992020799A1 JP 9200650 W JP9200650 W JP 9200650W WO 9220799 A1 WO9220799 A1 WO 9220799A1
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Japanese (ja)
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Hideaki Hagiwara
Yasuyuki Aotsuka
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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
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to antigens useful in a wide range of fields such as medical and pharmaceutical fields such as prevention, treatment and diagnosis of human diseases, pharmacology such as biochemical reagents and biopolymer purification reagents, and biochemical fields. It relates to the structure of the variable region of specific human immunoglobulin. More specifically, the present invention relates to a heavy chain of a cancer cell antigen-specific human immunoglobulin produced by a human Z human fusion cell line CL NZ SUZHI 1 of a B cell of a human uterine cancer patient and a human lymphoblast cell line. And the amino acid sequence of the light chain variable region and the nucleotide sequence of the gene.
  • Japanese Patent Application Laid-Open No. 58-201994 Japanese Patent Publication No. 01-59878
  • Japanese Patent Application Laid-Open Nos. 59-135898 and 59-137497 As disclosed in detail, a cell line CLNZSUZ HI 1 (ATCC No. HB8307) producing a human monoclonal antibody having high reactivity to human cancer cells was established.
  • the antibody (CLN-IgG) produced by this cell line has an antibody class of IgG, isotypes y1 and / c, and immunohistologically binds to the ⁇ antigen present on the surface of cancer cells.
  • more interesting findings have been obtained on the effect of suppressing the growth of cancer cells.
  • Monoclonal antibody-producing cell lines are generally known to decrease their antibody productivity with passage. Also, generally speaking, human hybridomas produce less antibody than mice. When human monoclonal antibodies are used for immunotherapy or diagnosis, a large amount of antibodies is required, and the solution of this problem is essential.
  • a main object of the present invention is to elucidate the gene structure of the light chain and heavy chain of the CLN-IgG monoclonal antibody.
  • the present inventors separated cDNAs encoding the light chain and heavy chain of the CLN-IgG monoclonal antibody, elucidated the DNA base sequence, and, based on the sequences, the light chain and heavy chain variable regions of the antibody.
  • the amino acid sequence of was determined, and the present invention was completed.
  • niRNA was prepared from CLNZSUZ HI1, and the cDNA A lambda phage 'library' prepared therefrom was screened by the plaque hybridization method, and the isolated phage clone was used. This was achieved by determining the nucleotide sequence of the inserted DNA.
  • the present invention will be described in more detail.
  • FIG. 2 shows a Kabat & Wu plot of 21 variable region sequences belonging to human heavy chain subgroup 3.
  • the DNA sequences of the light chain variable region and heavy chain variable region of the CLN-IgG monoclonal antibody can be determined using the human antibody gene fragment amplified by PCR (polymerase chain reaction) as a probe. It is determined by cloning the monoclonal antibody light chain and heavy chain cDNA and analyzing the DNA nucleotide sequence.
  • PCR polymerase chain reaction
  • the cell line used in the present invention is a human Z human hybridoma obtained by fusing human uterine cancer patient lymphocytes and human lymphoblasts. Specifically, the cell line is disclosed in Japanese Patent Application Laid-Open No. 58-201994 (Japanese Patent Publication No. 01-59878). Publication No. 2), which produces a human-type monoclonal antibody that specifically reacts with the cell surface antigen of cancer cells such as human brain tumors, lung cancer, stomach cancer, and malignant melanoma. It is.
  • This hybridoma is registered with ATCC (American Type Culture Collection) under the registration number HB8307.
  • the resulting poly (A) + RNA can be further used for preparing a cDNA library.
  • total RNA is extracted from CLN-SUZH11 hybridoma cells, and poly (A) + RNA is purified from this extract using an oligo dT cellulose column, and the following cDNA is prepared.
  • the library was used for construction.
  • an EcoRI linker can be ligated to the cDNA thus obtained, followed by digestion with EcoRI to introduce a sticky end.
  • the obtained fragment is ligated to an EcoRI site of an appropriate phage vector, for example, a ⁇ £ ⁇ 10 vector or an igtl1 vector, and then subjected to in vitro packaging to prepare a cDNA library. Can be made.
  • a human immunoglobulin light or heavy chain constant region or variable region gene or a fragment thereof, or a chemically synthesized oligonucleotide having a nucleotide sequence corresponding to the amino acid S sequence in that portion is used.
  • those labeled with 32 P, biotin or the like by the nick translation method can be used.
  • a fragment amplified by PCR in which the cDNA is subjected to type III and sequences corresponding to a part of the light chain and heavy chain of the antibody in a primer sequence is biotinylated by the nick translation method. Things can be used as probes.
  • the ICLN-G111 and the EcoRI fragment of ICLN-K411 obtained in the step [4] are recloned into pBluescript SK + and then infected with helper phage R408. Single-stranded DNA was prepared and its nucleotide sequence was determined by the Sanger method.
  • the method for obtaining the mRNA fraction from the human hypride dorma CLNZSUZ HI1 is as follows.
  • RNA was obtained from the total RNA fraction obtained by the above method by the method of Chirgwin [Chirgwin, J. ⁇ ⁇ , Przybyla, A. E-, MacDonald, RJ, & Rutter, WJ ( 1979) Biochemistry, 18, 5294-5299].
  • the solution is applied to an oligo (dT) cell source column that has been equilibrated with a binding buffer (0.5 M lithium chloride, 0.2% SDS, 1 OmM triethanolamine hydrochloride, pH 7.4) in advance. Further wash with 10 column volumes of binding buffer. You.
  • the poly (A) + RNA bound to the column is eluted with elution buffer (1 OmM triethanolamine hydrochloride, pH 7.4), and the RNA fraction is collected.
  • the resulting poly (A) + RNA solution is heat-treated at 100 ° C for 5 minutes, and the above-mentioned chromatography using an oligo (dT) cellulose column is repeated once again using a new column.
  • RNA For RNA, add 2.5 volumes of ethanol and 1/10 volume of 2M sodium acetate to the eluate, and recover as a precipitate after centrifugation at 10,000 xg. Dissolve the purified poly (A) + RNA precipitate in sterile pure water and store at 2 70 g at a concentration of 2 zg / zl.
  • cDNA was synthesized according to the protocol of Amersham's cDNA synthesis kit and 3.2 ⁇ g was recovered. After treating this cDNA fragment with EcoRI methylase, the EcoRI linker was ligated using T4 DNA ligase. After EcoR I digestion, a cDNA fraction having an EcoR I end was recovered using an Amersham column.
  • a sequence having a homology with the partial amino acid sequence of the CLN-IgG heavy chain determined in Example 3 was searched from the NBRF protein database (NBRF-PDB; National Biomedical Research Foundation Protein Data Base).
  • VH26 entity H3HU26, Accession number A02047) was found to have the highest homology. Therefore, it corresponds to the N-terminal amino acid 10 residues of the VH26 DNA sequence (ID name: HSIGHAU, Accession number M17747) in the EMBL DNA database (EMBL-GDB; European Molecular Biology Laboratory Gene data Base).
  • 30 nucleotides (Primer No. 1) were synthesized.
  • 30 nucleotides (primer No. 2) corresponding to 10 amino acid residues at the C-terminal side of the DNA sequence of the heavy chain 1 CHI domain (EMBL-GDB; ID name HS I GCC4, Accession number J00228) were synthesized.
  • the CLNZSUZ HI lcDNA library obtained in Example 2 was subjected to plaque hybridization using the biotinylated probe obtained in Example 4 to obtain 13 positive clones.
  • One of these clones had about 1.6K base pairs of imported DNA, and this phage was named; ICLN-G111.
  • CLNZSUZ HI lcDNA library obtained in Example 2 was subjected to plaque hybridization using the biotinylated probe obtained in Example 4 to obtain 27 positive clones.
  • Clone 411 in this contains about 1.0 K base pairs of imported DNA, and this phage was named CLN-K411.
  • variable regions there are regions (variable regions) in which the sequences are different from certain regions (constant regions).
  • variable regions the regions that are particularly rich in variability are called hyper-variable regions (Hv regions), and there are three heavy chains and three light chains. From the amino terminus, they are called Hvl, ⁇ 2, and Hv3, respectively.
  • Hv regions hyper-variable regions
  • Hvl, ⁇ 2, and Hv3 hyper-variable regions
  • CDR complementarity determining region
  • the amino acid sequence of the CLN-IgG light chain revealed that it belongs to kappa chain subgroup 1. Therefore, 24 sequences belonging to subgroup 1 contained in the NBRF-PDB (rel. 26) were arranged together with the CLN-IgG light chain, and the mutation degree was calculated at each position to create a Kabat & Wu plot (Fig. 1) From the results, Hvl, ⁇ 2, and Hv3 were determined as residue numbers 28 to 34, 50 to 56, and 91 to 96, respectively.
  • Hv2 Ala Ala Ser Ser Leu His Arg
  • the amino acid sequence of the heavy chain of CLN-IgG revealed that it belongs to Hv subgroup 3. Therefore, the Kabat & Wu plot was prepared by calculating the mutation degree at each position by juxtaposing the 21 sequences belonging to subgroup 3 contained in the NBRF-PDB (rel. 26) together with the CLN-IgG heavy chain (Fig. 2). , Up to residue number 96). As a result, Hvl and Hv2 were determined as residue numbers 31 to 35 and 49 to 59, respectively. Regarding Hv3, in the case of heavyweight, as shown in Table 3 below, it is difficult to exactly match the positions because the length of each sequence is significantly different.
  • the residue number is 1.0 for 96 cysteine, 2.1 for 97 glycine, 3.9 for 98 arginine, 29.3 for 99 valine, 18.4 for 109 tyrosine, 3.5 for 111 tributophan, 111 for 111 Glycine is 1.0.
  • the degree of mutation is high at residues 99 to 109, and this region is H Is equivalent to
  • Hv2 Ser Alalie Thr Pro Ser Gly Gly Ser Thr Asn
  • Hv3 Val Pro Tyr Arg Ser Thr Trp Tyr Pro Leu Tyr 3 Table
  • CAK GYIWNGNWFDSWGQGTLVTVS was CAR FRQ PFVQFFDVFGQGTLVT Bur CAK LIAVAG - TRDFWGQGTLVTVSL Tur CAR LSVTAVAFDVWGQGTKVS Til CAK GKVSAYYFDYWGEGTLVTVS S zap CAR TRPGGYFSDVWGQGTLVS Nie CAR IRDTAMFFAHWGQGTLVTVS S Jon CAR VWS TSMDVWGQGTPVT Gal CAR GWGGGDYWGQGTLVTVST But CAR DLAAARLFGKGTTVTVS S
  • the elucidation of the CL N-IgG antibody and its gene structure makes it possible to introduce this gene into animal cells and host cells such as Escherichia coli and express it, thereby obtaining a large amount of the antibody. Furthermore, not only complete antibodies, but also certain antibody fragments, such as heavy chains only, light chains only, Fab fragments, F (ab) ' 2 fragments, FV fragments, domain fragments (dAb), CDR fragments and other antibody-derived fragments Can be obtained. Further, by causing artificial mutations in the antibody gene, complete antibodies or fragments derived from various antibodies whose amino acid sequences are partially different can be obtained.
  • CLN-IgG acts on human cancer cells such as human stomach cancer, lung cancer, brain tumor, and malignant melanoma, and suppresses the growth of these cancer cells by its own action. Is expected to kill cancer cells and further suppress cancer cell growth with the help of traps or K-cells and macrophages, and to kill cancer cells.
  • CLN-IgG gene by modifying the CLN-IgG gene and partially substituting the amino acids of the antibody, it is possible to further increase the activity of the antibody. For example, it can be modified so as to increase the binding affinity to an antigen, the anticancer activity via an immunocompetent cell, or the invasiveness to a tissue.
  • cytotoxicity, enzymatic activity, immunity-inducing activity, etc. are added to an antibody molecule or a fragment thereof at the gene level by adding toxicity, enzyme activity, immunity-inducing activity, etc. to the antibody molecule or a fragment thereof at the gene level. It is conceivable to design a molecule having a higher anticancer activity.
  • Specific examples include the use of cancer-specific antibodies as carriers, for example, chemotherapeutic agent binding-human monoclonal antibody, interferon binding-human monoclonal antibody, high molecular weight toxin binding It is useful as a drug that induces cancer cell growth inhibition or death in the form of a monoclonal antibody, drug-containing ribosome binding-human monoclonal antibody, and the like.
  • radiosensitizers may be conjugated to antibodies and administered to patients, selectively accumulate in spheroid cells, and improve therapeutic and diagnostic effects.
  • a complete antibody may be used as a human monoclonal antibody, or as described above, for example, only a heavy chain, only a light chain, a Fab fragment, an F (ab) ' 2 fragment, Smaller fragments containing specific antigen recognition sites, such as v-fragments, domain fragments (dAbs), and CDR fragments can also be used.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Immunology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Cell Biology (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Peptides Or Proteins (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

Séquences d'acides aminés des régions variables à chaîne lourde et à chaîne légère de l'immunoglobuline CLN-IgG humaine spécifique d'antigènes de cellules cancéreuses produite par la lignée cellulaire fusionnée humaine/humaine CLN/SUZ H11 composée des cellules B d'une patiente présentant un cancer de l'utérus et de la lignée cellulaire des lymphoblastes humains; et séquences de bases des gènes relatifs. Ces séquences d'acides aminés et de bases sont utiles en médecine et dans l'industrie pharmaceutique pour la prévention, le traitement et le diagnostic de maladies humaines, ainsi qu'en pharmacologie et en biochimie comme réactifs biochimiques et réactifs pour la purification de biopolymères.
PCT/JP1992/000650 1991-05-22 1992-05-21 Sequence d'acides amines d'anticorps monoclonal humain anticancer et sequence de bases d'adn codant pour ces acides amines Ceased WO1992020799A1 (fr)

Applications Claiming Priority (2)

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JP3/145218 1991-05-22
JP3145218A JPH04346792A (ja) 1991-05-22 1991-05-22 抗癌ヒトモノクローナル抗体のアミノ酸配列及びそれをコードするｄｎａ塩基配列

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997044461A3 (fr) * 1996-05-22 1998-05-07 Novopharm Biotech Inc Fragments de liaison a l'antigene detectant specifiquement des cellules cancereuses, nucleotides codant lesdits fragments, et leur utilisation pour la prophylaxie et le depistage de cancers
EP0971034A4 (fr) * 1996-11-19 2005-02-23 Hagiwara Yoshihide Procede pour preparer des molecules d'anticorps
US7115722B1 (en) 1997-05-22 2006-10-03 Viventia Biotech, Inc. Antigen binding fragments that specifically detect cancer cells, nucleotides encoding the fragments, and use thereof for the prophylaxis and detection of cancers
US20120128723A1 (en) * 2004-12-21 2012-05-24 Viventia Biotechnologies Inc. Cancer specific antibody and cell surface proteins

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07101999A (ja) * 1993-10-06 1995-04-18 Hagiwara Yoshihide 抗癌ヒトモノクローナル抗体に対する抗イデイオタイプ抗体のアミノ酸配列およびそれをコードするｄｎａ塩基配列

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS58201994A (ja) * 1982-05-21 1983-11-25 Hideaki Hagiwara 抗原特異的ヒト免疫グロブリンの生産方法
JPS59135898A (ja) * 1983-01-20 1984-08-04 ザ・リ−ジエンツ・オブ・ザ・ユニバ−シテイ・オブ・カリフオルニア 抗原特異的ヒト免疫グロブリンの生産方法
JPS59137497A (ja) * 1983-01-20 1984-08-07 ザ・リ−ジエンツ・オブ・ザ・ユニバ−シテイ・オブ・カリフオルニア 抗原特異的免疫グロブリン生産性ヒト／ヒトハイブリド−マ及びその生産する抗体

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS58201994A (ja) * 1982-05-21 1983-11-25 Hideaki Hagiwara 抗原特異的ヒト免疫グロブリンの生産方法
JPS59135898A (ja) * 1983-01-20 1984-08-04 ザ・リ−ジエンツ・オブ・ザ・ユニバ−シテイ・オブ・カリフオルニア 抗原特異的ヒト免疫グロブリンの生産方法
JPS59137497A (ja) * 1983-01-20 1984-08-07 ザ・リ−ジエンツ・オブ・ザ・ユニバ−シテイ・オブ・カリフオルニア 抗原特異的免疫グロブリン生産性ヒト／ヒトハイブリド−マ及びその生産する抗体

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997044461A3 (fr) * 1996-05-22 1998-05-07 Novopharm Biotech Inc Fragments de liaison a l'antigene detectant specifiquement des cellules cancereuses, nucleotides codant lesdits fragments, et leur utilisation pour la prophylaxie et le depistage de cancers
US6207153B1 (en) 1996-05-22 2001-03-27 Viventia Biotech, Inc. Antigen binding fragments that specifically detect cancer cells, nucleotides encoding the fragments, and use thereof for the prophylaxis and detection of cancers
US7166286B2 (en) 1996-05-22 2007-01-23 Viventia Biotech Inc. Antigen binding fragments that specifically detect cancer cells, nucleotides encoding the fragments, and use thereof for prophylaxis and detection of cancers
EP0971034A4 (fr) * 1996-11-19 2005-02-23 Hagiwara Yoshihide Procede pour preparer des molecules d'anticorps
US7115722B1 (en) 1997-05-22 2006-10-03 Viventia Biotech, Inc. Antigen binding fragments that specifically detect cancer cells, nucleotides encoding the fragments, and use thereof for the prophylaxis and detection of cancers
US20120128723A1 (en) * 2004-12-21 2012-05-24 Viventia Biotechnologies Inc. Cancer specific antibody and cell surface proteins
US8697075B2 (en) * 2004-12-21 2014-04-15 Viventia Bio Inc. Cancer specific antibody and cell surface proteins

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AU1875592A (en) 1992-12-30

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