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WO1996027010A1 - Anticorps chimere monoclone murin et human, ou un fragment de cet anticorps, specifique du recepteur egf - Google Patents

Anticorps chimere monoclone murin et human, ou un fragment de cet anticorps, specifique du recepteur egf Download PDF

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Publication number
WO1996027010A1
WO1996027010A1 PCT/EP1996/000805 EP9600805W WO9627010A1 WO 1996027010 A1 WO1996027010 A1 WO 1996027010A1 EP 9600805 W EP9600805 W EP 9600805W WO 9627010 A1 WO9627010 A1 WO 9627010A1
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WO
WIPO (PCT)
Prior art keywords
chmint5
seq
antibody
fragment
ser
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Application number
PCT/EP1996/000805
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English (en)
Inventor
Antonio Mele
Rita De Santis
Cristina Ferrer Marsal
Anna Maria Anastasi
Anna Maria Di Massimo
Maria Ines Colnaghi
Original Assignee
Ministero Universita' Ricerca Scientifica E Tecnologica
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Publication date
Application filed by Ministero Universita' Ricerca Scientifica E Tecnologica filed Critical Ministero Universita' Ricerca Scientifica E Tecnologica
Priority to AU47191/96A priority Critical patent/AU4719196A/en
Publication of WO1996027010A1 publication Critical patent/WO1996027010A1/fr

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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
    • C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide

Definitions

  • This invention relates to a murine/human chimeric monoclonal antibody, termed chMint5. which is specific for the EGF-receptor. Particularly, the nucleotide sequences and the amino acid sequences encoded by them of the variable regions (VH and VL) of such chimeric antibody, chMint5, are disclosed.
  • VH and VL variable regions
  • Anterior Art Mint5 is a monoclonal antibody specific for the EGF-receptor (EGF-R), obtained by immunization of mice with A431 cell line.
  • Mint5 has got an inhibitory effect on growth of cells having high levels of EGF-R expression in experiments either in vivo or in vitro, but it has got no effect on cells having normal levels of receptor expression.
  • Mint5 is efficiently internalized. Moreover, capability of inhibiting growth of tumor cells which were transplanted in athymic mice was shown.
  • the cell line of hybridoma producing Mint5 antibody was filed in 1993. the seventh of September, by DSM (Deutsches Sammlung von Mikroorganismen und Zellkulturen GmbH) with number ACC2150.
  • the variable domains are determining for the antigenic identification of the tumor cell.
  • the murine origin of such antibody limits its use in clinical therapy owing to the immune response of the host receiver.
  • chMint5. a novel chimeric monoclonal antibody which could show a lower immnunogenicity when administered to humans.
  • this invention relates to a chimeric monoclonal chMint5 antibody or to a fragment thereof comprising a certain amino acid sequence of the variable regions of the heavy chain (VH) and light chain (VL) of the monoclonal antibody obtained by the hybridoma deposited as DSM ACC2150 (murine Mint5).
  • This invention relates, therefore, to nucleotide sequences coding the variable regions of the heavy chains (VH) and light chains (VL) of chMint5 antibody, to the correspondent amino acid sequences and it also relates to chMint5 antibody and to the fragments thereof comprising said sequences of the variable regions, and comprising whole constant regions or parts thereof of the heavy and light chains obtained from human i munoglobulins.
  • chMint5 antibody can be used alone or combined to cytotoxic molecules according to the present invention in the antitumor therapy of patients affected by tumors characterized by a high level of EGF-R expression in a diagnostic assay specific for the determination of the EGF-R.
  • This diagnostic method comprises a ligand or a conjugate (e.g. another antibody), eventually labeled or bound to a chromogen, which recognize the variable regions of said chMint5. Description of Figures and List of the Sequences
  • FIG. 1 shows a schematic illustration of the cDNA amplification of the heavy chain (H) of chMint5- - 3 -
  • FIG. 2 shows a schematic illustration of the procedure of chMint5 expression in CHO cells.
  • FIGS. 3A and 3B show FACS analysis (Fluorescence Activated Cell Sorter) of chMint5 on EGF-R + and EGF-R " cell lines.
  • the cells (1X10 6 ) were incubated into ice for 30 minutes, with chMint5 or PBS/13.FCS (negative control). The cells were then washed with PBS/l ⁇ FCS and incubated with FITC-conjugated anti-human-IgGl murine antibody
  • FIG. 4a shows the affinity constant of murine Mint5 bound on A431 cells. The characteristics are the following:
  • - SEQ ID N0:1 sequence shows the nucleotide and amino acid sequences of the variable region of the chM ⁇ nt5 antibody heavy chain.
  • - SEQ ID NO:2 sequence shows the amino acid sequence (deduced from the nucleotide sequence indicated in SEQ ID N0:1) of the variable region of the chMint5 antibody heavy chain.
  • SEQ ID NO:3 sequence shows a N-terminal fragment of the amino acid sequence of the variable region of the heavy chain. Said sequence was determined by means of Edman degradation. Only No. 1,3.5 and 6 amino acids differ from the deduced amino acid chain indicated in SEQ ID N0:2. Amino acids indicated as Xaa were not correctly defined. As these didn't influence the identification of the variable region, the antibody was not subjected to further analysis of the proteic sequence.
  • sequence shows the nucleotide and the amino acid sequences of the variable region of the chMint5 antibody light chain.
  • the nucleotide sequence of eight codons (24 nucleotides) at 5'- and 3'- ends were established by primers used in the cDNAs amplification by means of PCR. Sequences indicated as CDR1, CDR2 and CDR3 refer to hypervariable regions.
  • - SEQ ID NO: sequence shows the amino acid sequence (deduced by the nucleotide sequence indicated in SEQ ID NO: ) of the variable region of the chMint5 antibody light chain.
  • - SEQ ID NO:6 sequence shows a N-terminal fragment of the amino acid sequence of the variable region of the chMint5 antibody light chain. Said sequence was determined by means of Edman degradation. Only No. 3 and 8 amino acids differ from the deduced amino acid sequence indicated in SEQ ID NO:5- Amino acids indicated as Xaa were not correctly defined. As these didn't influence the identification of the variable region, the antibody was not subjected to further analysis of the proteic sequence.
  • SEQ ID NO:7 shows the nucleotide sequence of a 5' primer specific for the leader sequence of the light and heavy chains for use in PCR.
  • - SEQ ID NO:8 shows the nucleotide sequence of CKhu primer specific for the constant region of the light chain for use in PCR.
  • - SEQ ID NO: shows the nucleotide sequence of the antisensus VH1F0R primer specific for the sequence of a fragment of the constant region of the heavy chain for use in PCR.
  • - SEQ ID NO: 10 shows the nucleotide sequence of the CHhu primer specific for the sequence at the 3 '-end of the constant region fragment of the heavy chain for use in PCR.
  • Murine/human chimeric monoclonal chMint5 antibody was obtained by fusion of the genes of the variable regions of the light and heavy chains of murine Mint5 antibody at the nucleotide sequences coding for human immunoglobulin constant regions.
  • VH and VL nucleotide sequences were bound to the nucleotide sequences of human C-gammal and
  • RNA from Mint5 hybridomas was isolated and VH and VL genes were obtained by amplification by means of PCR, using consensus primers.
  • the amplified VH and VL genes were cloned in M13- derived vehicles (in M13VHPCR1 vehicle and in M13VKPCR1 vehicle respectively, courteously given by Dr.G. inter) containing the promoter and the leader sequence of the immunoglobulin genes. and then sequenced.
  • VH fragment gene was directly cloned in M13VHPCR1 vehicle and sequenced (Sequenase Version 2.0 U.S.B., USA). Instead, the VL gene (then indicated as VK, too) was at first introduced in M13mpl9 vehicle in order to remove the two inside BamHI and PvuII restriction sites, by means of site-directed mutagenesis (Oligonucleotide-Directed In vitro mutagenesis System Version 2. Amersham International pic. Little Chalfont. UK). These restriction sites would have hinder the VK insertion into M13VKPCR1 vehicle and the subcloning in the vehicle of expression for the chimeric light chain (alfa-Lysl7 vehicle). The thus modified VK gene was then cloned in M13VKPCR1 vehicle and at last sequenced.
  • VH and VK genes of Mint5 were inserted in alfa-Lys30 and alfa-Lysl7 vehicles, respectively (courteously given by Dr.G.Winter) .
  • Alfa-Lys30 plasmid contains the human Cgammal chain gene and gpt gene (xanthine-guanine phosphoribosyl transferase) as selection marker.
  • pMRSl ⁇ vehicle of expression was therefore prepared.
  • Said vehicle of expression was obtained by cloning Hindlll-BamHI fragment, obtained from M13VHPCR1 vehicle, which contains the promoter, the leader sequence and the Mint5 VH region in alfa-Lys30 vehicle, upstream from the human constant region gene.
  • Alfa-Lysl7 plasmid contains the human CK chain gene and the gene for resistance to hygromicine as selection marker.
  • pMRS17 vehicle of expression was therefore prepared.
  • Said vehicle of expression was obtained by cloning Hindlll-BamHI fragment, obtained from M13VKPCR1 vehicle which contains the promoter, the leader sequence and the Mint5 VK region in alfa-Lysl7 vehicle, upstream from the human constant region gene.
  • non- secernent-immunoglobulin murine myeloma NSO/1 cells were cotransfected with pMRSl ⁇ and pMRS17 vehicles by means of electroporation (Potter et al.. 1984, PNAS, 81:7l6l-7l65) .
  • the stable transfectans were analyzed and selected according to their mycophenolic acid resistance and hygromicine resistance and according to the chimeric antibody production by means of ELISA.
  • the transfectomas in NSO cells showed chMint5 productivity of 1-5 ng/10 cells/24 hours. These productivity levels, although they didn't allow the preparatory purification of the chimeric antibody, showed that chMint5 genes are correctly translated by transfected NSO/1 cells which can be then utilized for the isolation of cDNAs of the chMint5 heavy and light chains in order to achieve a better expression.
  • Example 2
  • the primers utilized in PCR for the amplification of the chMint5 cDNAs are indicated in the following Table.
  • a leader primer CKhu (SEQ ID N0:7) (SEQ ID N0:8)
  • A cDNA of the light chain
  • B cDNA of the fragment of the variable region of the heavy chain
  • C cDNA of the fragment of the constant region of the heavy chain ' 'VH1F0R primer was described in Orlandi et al., (as above). PCR was performed by using leader primers complementary to the 5'- leader region of the heavy and light chains by inserting a Xbal site. For human heavy and light constant 3' regions, CHhu and CKhu primers respectively were used, primers which introduce a Smal site.
  • the cDNA of the chimeric heavy chain was amplified in two phases (according to the scheme of Figure 1): a) the leader and variable regions were amplified by using a leader primer at the 5'-end and VHIFOR primer at the 3'-end; the constant region was amplified by using, at the 5'-end, antisensus VHIFOR primer (complementary to VHIFOR primer), and CHhu primer at 3'-end; b) products of such amplifications were amplified once again, all together in order to achieve the whole heavy chain.
  • pMRS ⁇ l and pMRS71 Two pSV2-derived vehicles, termed pMRS ⁇ l and pMRS71 were used to express the genes of the chMint5 heavy and light chains respectively, in CHO cells.
  • pMRS ⁇ l was obtained from pMCMVbeta51-2. This vehicle was digested with AccI and Hindlll, thus eliminating the immediate early promoter of murine Cytomegalovirus. At Accl-Hindlll sites the immediate early promoter of human cytomegalovirus was cloned, with Accl-Hindlll end (promoter which was disclosed in Int. Appln. No. W095/H982 filed on October 24. 1994. In this way, pUthCMVbeta vehicle was obtained.
  • pMRS71 was obtained from pMCMVbeta51-2 vehicle.
  • pMCMVbeta51-2 vehicle was linearized with BamHI and treated with alkaline fosphatase from intestinal calf ucosa (CIP); in the thus treated vehicle, the transcription VIDHFR unit was inserted.
  • CIP intestinal calf ucosa
  • pMCMVbeta51-2 vehicle and the transcription VIDHFR unit are mentioned in Int. Appln. No. W095/H982 filed on October 24, 1994.
  • pMRS ⁇ l is, therefore, a plasmid containing the early promoter of human Cytomegalovirus, the polyadenylation signal of the 1-betaglobin of rabbit and the gtp gene as selection marker.
  • cDNA of the chMint5 heavy chain was cloned in Xbal-Smal cloning site as Xbal-blunt fragment owing to the presence of an inside Smal site in the human constant region.
  • the thus obtained vehicle was termed pMRS ⁇ 9- cDNA of the chimeric light chain, amplified from transfected NSO/1 cells, was cloned as a Xbal-Smal fragment in pMRS71 plasmid containing the early promoter of murine Cytomegalovirus, the polyadenylation signal of 1-betaglobin of rabbit and the gene of dihydrofolate reductase (dhfr) as amplificable selection marker.
  • CHO dhfr " cell line was cotransfected with pMRS ⁇ 9 and pMRS95 vehicles (see Figure 2) by lipofection (Feigner P. et al., 19 ⁇ 7. PNAS, ⁇ 4, 7413-7417).
  • the transfectants were selected according to the dhfr + /gpt double resistance phenotype.
  • the single clones were moved to 24-well plates and after one week of growth, the supernatants of culture were tested for production of chMint5 by ELISA.
  • Such transfectant clones secreted amounts of chMint5 from 0 to 100 ng/10° cells/24 hours.
  • Mint5 antibody was purified from supernatants of cultures of a CHO transfectant single clone, by means of affinity chromatography on A Protein-Sepharose. The binding activity of the chimeric antibody was analyzed by means of flow cytometry. A 31 cells of human epider oid carcinoma and human Jurkat T EGF-R negative cells were used in the assay. The results, illustrated in Figure 3.
  • chMint5 specifically recognizes the A431 cells (EGF-R + ), but it doesn't bind the Jurkat T cells (EGF-R " ).
  • the binding affinity constants for murine and chimeric antibodies were determined by means of the titration curves of the monoclonal antibody, obtained by IRMA on A431 target cells.
  • Figures 4a and 4b show a Kaff value (affinity constant) of 6.76X10 ⁇ M " for chMint5. whereas Mint5 value was 2.05X10 M ⁇ , thus indicating that chMint5 substantially keeps the binding affinity properties of the murine Mint5-
  • chMint5 antibody showed to keep the specificity and the binding affinity properties of the murine Mint5 antibody. chMint5 also shows a greater utilization in the human tumor therapy.
  • chMint5 antibody can be used for the preparation of a pharmaceutical composition, useful in human therapy, comprising a pharmaceutically acceptable carrier and/or excipient. chMint5 can be also used in the preparation of immunotoxins or immunocytokines.
  • Such immunotoxins or immunocytokines can be obtained by means of chemical conjugation or by recombination of genes which correspond to chMint5 or to parts of it and by recombination of genes coding for the toxins or the cytokines which will be in the immune-complex. Further this invention relates to the use of such immunotoxins or immunocytokines for the preparation of pharmaceutical compositions useful in the human antitumor therapy, combined to a pharmaceutical acceptable carrier and/or excipient. chMint5 can be also used in a diagnostic test specific for the EGF-R.
  • Such diagnostic method comprises the chMint5 antibody and a ligand or a conjugate (for example another antibody), eventually labeled or bound to a chromogen, which recognize the variable regions of said chMint5.
  • a ligand or conjugate for example another antibody
  • such ligand or conjugate will comprise a sequence complementary to at least one of the sequences indicated in SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:5.
  • GCA TAC ATT AGT AAT GGT GGT GGT AGC ACC TAT TAT CCA GAC ACT GTA 1 Ala Tyr lie Ser Asn Gly Gly Gly Ser Thr Tyr Tyr Pro Asp Thr Val 50 55 60
  • Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80
  • MOLECULE TYPE DNA
  • ANTI-SENSE YES
  • FEATURE VHIFOR anti-sense primer specific for the sequence of a fragment of the constant region of the heavy chain for use in PCR

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

La présente invention concerne un anticorps chimère monoclone murin et humain (désigné par chMint5), obtenu par le chMint5 monoclone murin, qui est spécifique du récepteur EGF. En particulier, elle porte sur les séquences de nucléotides et les séquences d'acides aminés, encodées par elles, des régions variables (VH et VL) d'un tel anticorps chMint5.
PCT/EP1996/000805 1995-03-01 1996-03-01 Anticorps chimere monoclone murin et human, ou un fragment de cet anticorps, specifique du recepteur egf WO1996027010A1 (fr)

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AU47191/96A AU4719196A (en) 1995-03-01 1996-03-01 Murine/human chimeric monoclonal antibody or a fragment thereof specific for the egf receptor

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IT95FI000036A IT1277827B1 (it) 1995-03-01 1995-03-01 Anticorpo monoclonale chimerico murino/umano o un suo frammento specifico per il recettore egf (egf-r)
ITFI95A000036 1995-03-01

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7582296B2 (en) * 2002-07-31 2009-09-01 D. Collen Research Foundation Vzw Anti-idiotypic antibodies against factor VIII inhibitor and uses thereof
US8277805B2 (en) 2003-08-14 2012-10-02 Life Sciences Research Partners Methods for treating or inhibiting thromboembolic disorders or for inhibiting coagulation
US8309086B2 (en) 1999-07-14 2012-11-13 Life Sciences Research Partners Vzw Antibodies which bind factor VIII
WO2016062851A1 (fr) 2014-10-23 2016-04-28 Innate Pharma Traitement des cancers au moyen d'agents anti-nkg2a
WO2020136147A1 (fr) 2018-12-26 2020-07-02 Innate Pharma Composés et méthodes de traitement du cancer de la tête et du cou
CN111647564A (zh) * 2020-05-18 2020-09-11 李欣 抗eb病毒lmp1的单克隆抗体及其细胞株和应用

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WO1992015683A1 (fr) * 1991-03-06 1992-09-17 MERCK Patent Gesellschaft mit beschränkter Haftung Anticorps monoclonaux humanises et chimeriques
EP0586002A2 (fr) * 1992-08-18 1994-03-09 CENTRO de IMMUNOLOGIA MOLECULAR Anticorps monoclonaux contre le récepteur du facteur épidermique de croissance, cellules et méthodes pour leur préparation et compositions qui les contiennent
WO1995007297A1 (fr) * 1993-09-06 1995-03-16 Menarini Ricerche Sud S.P.A. Proteines d'inactivation de ribosomes extraites de graines de $(saponaria ocymoides) et de vaccaria pyramidata, leur preparation et immunotoxines les contenant

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S. MUNOZ ET AL.: "Biochemical and toxic properties of an immunotoxin composed of an anti-EGFR mouse mAb and the RIP alpha-sarcin.", EUROPEAN JOURNAL OF CANCER, vol. 27, no. suppl. 3, 1991, OXFORD, GB, pages S82, XP000570465 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8309086B2 (en) 1999-07-14 2012-11-13 Life Sciences Research Partners Vzw Antibodies which bind factor VIII
US8784816B2 (en) 1999-07-14 2014-07-22 Life Sciences Research Partners Vzw Antibodies which bind factor VIII
US7582296B2 (en) * 2002-07-31 2009-09-01 D. Collen Research Foundation Vzw Anti-idiotypic antibodies against factor VIII inhibitor and uses thereof
US8277805B2 (en) 2003-08-14 2012-10-02 Life Sciences Research Partners Methods for treating or inhibiting thromboembolic disorders or for inhibiting coagulation
US8282923B2 (en) 2003-08-14 2012-10-09 Life Sciences Research Partners Antibodies which bind and inhibit blood factor VIII
US8293234B2 (en) 2003-08-14 2012-10-23 Life Sciences Research Partners Antibodies which bind and inhibit blood factor VIII
WO2016062851A1 (fr) 2014-10-23 2016-04-28 Innate Pharma Traitement des cancers au moyen d'agents anti-nkg2a
EP3659625A1 (fr) 2014-10-23 2020-06-03 Innate Pharma Traitement de cancers à l'aide d'agents anti-nkg2a
WO2020136147A1 (fr) 2018-12-26 2020-07-02 Innate Pharma Composés et méthodes de traitement du cancer de la tête et du cou
CN111647564A (zh) * 2020-05-18 2020-09-11 李欣 抗eb病毒lmp1的单克隆抗体及其细胞株和应用
CN111647564B (zh) * 2020-05-18 2023-07-04 李欣 抗eb病毒lmp1的单克隆抗体及其细胞株和应用

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ITFI950036A0 (it) 1995-03-01
AU4719196A (en) 1996-09-18
ITFI950036A1 (it) 1996-09-01
IT1277827B1 (it) 1997-11-12

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