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WO1999019361A1 - Molecules de fixation contre des complexes recepteur-ligand - Google Patents

Molecules de fixation contre des complexes recepteur-ligand Download PDF

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Publication number
WO1999019361A1
WO1999019361A1 PCT/EP1998/006386 EP9806386W WO9919361A1 WO 1999019361 A1 WO1999019361 A1 WO 1999019361A1 EP 9806386 W EP9806386 W EP 9806386W WO 9919361 A1 WO9919361 A1 WO 9919361A1
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WO
WIPO (PCT)
Prior art keywords
receptor
ligand
binding molecules
molecules according
binding
Prior art date
Application number
PCT/EP1998/006386
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German (de)
English (en)
Inventor
Klaus Bosslet
Heike Petrul
Original Assignee
Klaus Bosslet
Heike Petrul
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Klaus Bosslet, Heike Petrul filed Critical Klaus Bosslet
Priority to AU11518/99A priority Critical patent/AU1151899A/en
Publication of WO1999019361A1 publication Critical patent/WO1999019361A1/fr

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Classifications

    • 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
    • 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

Definitions

  • B i ndemo I eku Ien against receptor-ligand complexes makes it possible to use structures that are selectively associated with a disease as a target for therapeutic agents.
  • enzymes are neither selective for the disease nor overexpressed in the disease to be treated. This lack of selectivity often causes undesirable effects on normal tissues, which adversely affect the tolerance of the pharmaceutical (enzyme inhibitor).
  • receptor antagonists Other drugs interact, for example, with receptor structures on the cell surface and inhibit the interaction of the receptor with its natural ligand (receptor antagonists). This prevents the transmission of a signal through the ligand via the receptor into the cell (blockage of the signal 11 transduction). Since the receptor / ligand interactions produced by the receptor antagonists in 11 and 11 just like the above-mentioned enzymes occur not only in diseased but also in healthy tissues, the use of receptor antagonists is also important mostly associated with adverse side effects.
  • Antibodies known to date are specifically directed against a receptor on the cell surface or a ligand (for example EP 0 696 456; Mi llauer et al. (1993), Cell 72, 835-846) and thus influence a receptor or its ligands even when at rest (kovent i one II e receptor antagonists).
  • binding molecules described in the present invention react with epitopes which are neither present on the receptor nor on the ligand aI I e i ne, but instead arise at the points at which a receptor interacts with its ligand.
  • Binding molecules that are specifically directed against the receptor (s) ligand (s) complex I ex are selective for the receptor in the activated state and are therefore selective for the region of the tissue that migrates.
  • Suitable binding molecules include antibodies, antibody fragments (scFV, DABs, CRABs, diabodies, M inif I exant i bo-dies, M ini ant i od i es, tetravalent mono- or polyspecific antibodies), peptides, cyclic peptides, peptides i - metica and derived low-molecular ulare synthetics.
  • the described (receptor (s) -L i gand (s) -comp I exe are target structures particularly suitable for therapeutic use for the reasons mentioned above.
  • the invention thus relates to binding demonstrations which are obtained by immunization or immunoselection with a receptor ligand copex, the receptor and ligand being linked to one another by at least one covalent bond, process for their manufacture as well as their use as pharmaceuticals or d i agnost iku.
  • the invention further relates to nucleic acid chemistry which codes for the antibodies, vectors or expression vectors which contain these nucleic acids, and to animals, cells or cell lines by means of which the antibodies mentioned can be produced .
  • the invention relates to B i ndemo I ek ü I e such as Antibodies or antibody fragments which are characterized in that they bind specifically to the receptor ligand component I ex.
  • a covalent bond between the receptor and ligand must be established for the production or immunization and immunization of the antibodies, whereas this is not necessary for the binding of the produced antibody to its epitope.
  • B i ndemo I ek ⁇ I e with specificity for a receptor complex can e.g. B. can also be obtained via the SELEX process (NeXstar Pharmaceuti ca I s Inc.). These B i ndemo I ek u I e are synthetic 0 I i gonuk I eot i de, so-called aptamers. A modification of these amptamers are the Spiegelmers (Nolte et al. (1996), Nature Biotechnology Igy 14, 1116-1119), which consist of nucleotides that do not occur naturally and therefore have a higher stability.
  • the term receptor means the following structures:
  • Molecules on cell surfaces that can bind a ligand, or parts thereof that can bind a ligand. These are, for example, proteins, glycol ipide or proteins modified by lipids, sugars, ribonucleic acid, phosphates, protoporphyrins, F a i nnuk I eot i de or metals.
  • Receptors are e.g. B. Tyros i nphosphok i nasen such as Fit 1, KDR, Tie, Tek. A summary of other suitable receptors is given in Table 1 and Appendix 1.
  • ligand means the following structures:
  • Solve molecules that bind to a receptor are, for example, proteins, glycol ipides, peptides, glycopeptides, 0 I i gosacchar i de, ni edermo I ek u I are synthetics, glycosides or by lipids, sugars, ribonucleic acids, phosphates, protoporphyrins, FI av i naden i nnuk I eot i de or Metal l modified proteins.
  • Ligands are e.g. B. VEGF, VEGF-B, VEGF-C, Interleukin 12, PIGF, TEKL-1, TEKL-2.
  • the covalent bond between receptor and ligand is preferably formed by a peptide or a bi-functional crosslinker.
  • a peptide or a bi-functional crosslinker In the case of protein receptors and carbohydrate II proteins, other covalent bonds can also be used.
  • Amino acid sequences can be used as peptide from 1 to 30 amino acids are used, e.g. B. the sequence (GI y * Ser) 3.
  • the covalent bond between receptor and ligand is produced, for example, in such a way that purified and / or unpurified receptor and ligand moecules with a bifunctional crosslinking agent such as Bis-Su I f osucc inii dy I suberate, N-5-azido-2-nitrobenzoyloxysuccinimide, N-hydroxysuccini idyl-4-azidobenzoate, p-nitrophenyl-2-diazo-3,3,3-trifluoro-propionate (Pierce, Rockford, I ll inois , USA) and then the covalently linked receptor-ligand complex is separated from the individual components.
  • a bifunctional crosslinking agent such as Bis-Su I f osucc inii dy I suberate, N-5-azido-2-nitrobenzoyloxysuccinimide, N-hydroxysuccini idyl-4-azidobenzo
  • Suitable immunogens or antigens are also recombinant fusion proteins, containing the sequences of a protein receptor, peptide - as a compound (linker) of receptor and ligand - and a protein or peptide.
  • Suitable antigens for the production of the antibodies according to the invention are also one, two or three identical or different receptors which can be covalently linked to one, two or three identical or different ligands.
  • the following receptor ligand compexes can result:
  • R1 and R? stand for two different receptors and L1 and Lz stand for two different ligands; "-" stands for a covalent bond between receptor and ligand.
  • the ligand can also be a homodimer or heterodimer.
  • Two identical receptors are preferably coupled with one ligand.
  • Example swe ise binds a vascular endothelial growth factor (VEGF) -L i gand to two kinase do ain insert re ceptor (KDR) receptors.
  • VEGF-binding domains are preferably bound to a VEGF ligand by a KDR receptor or an fms-like tyrosine kinase receptor (FI t receptor) as a soluble component.
  • Further possible and preferred receptor ligand compexes include those described in Shawver et al, Drug Discovery Today, Vo I 2; 50-63, 1993 receptors and ligands described in Figures 4 and 5.
  • the invention further relates to the following DNA sequences of a single-chain antibody fragment (scFv), which represents the variable domains of a light (Vi) and heavy (V H ) antibody chain connected via a linker (VH-Linker-V ⁇ ).
  • the linker has the sequence:
  • the DNA sequences 1-10 according to the invention code for scFV fragments which are directed against the sFLT / VEGF- Komp I ex (see example 1).
  • G ⁇ T GCC AAC GGA CC ⁇ CGG TTA CCG TTT TCT T ⁇ TCT GG ⁇ GCG GTT
  • the invention also relates to functionally equivalent variants of SEQ ID NO. 1 -10.
  • the term "functionally equivalent variants” stands for modifications of the DNA sequences and their corresponding amino acid sequences, which stand for the light and / or heavy antibody chain and which bind to the receptor ligand component, but essentially not to the receptor or ligand alone, and their correspondingly formed antibodies, in comparison with the antibodies coded by SEQ ID NO.1-10, has a similar affinity for the receptor ligand component I ex.
  • the affinity for sFLT-VEGF receptor-L-i gand Comp ex I (see. Example 1 p 18) determined by Scatchard Ana I ysis is from 10 3 I / mol to 10- 15 / mol, preferably from 10 - 7 I / mol to 10- Z I / mol.
  • Another object of the invention is a molecular construct consisting of the amino acid chain which is encoded by SEQ ID NO.1-10 or its analogs and further amino acid chains linked to the sequence mentioned, these amino acid chains being different from the inventions Sequences and preferably parts of a human
  • Antibodies are, for example, parts of the constant areas of the heavy and light chains.
  • Other molecular constructs are, for example, "single domain” fragments or “single chain” fragments.
  • the present invention also includes humanized monoclonal antibodies (humMAK) or functionally active parts thereof which contain the light antibody chains and heavy antibody chains according to the invention.
  • Functionally active parts thereof are, for example, F (ab) or F (ab ') 2 fragments with one or more hanging regions.
  • Functionally equivalent variants are also the complementary determination regions (CDRs) of the antibody sequences, and peptides or mimetics derived from the CDRs.
  • the molecular constructs according to the invention or the humMAK effector or reporter contain molecules, for example a chelate for complexation with metal ions (eg EDTA, DTPA), heterologous toxic enzymes (eg ricin), a second binding region of other specificity or with kata I yt i see properties and / or common or toxic or non-toxic enzyme derived from non-human primates.
  • the constructs according to the invention or the humMAK according to the invention can also be used, for example, according to the method of Schwarz (Schwarz, A. & Steinstasse, A. (1987), A novel approach to Tc-99 labeled monoclonal antibodies. J. Nuc I. Med., 28, 721) with Tc-99m or according to generally known methods with Re or Y. The marking with Tc-99m is preferred for the diagnostic area.
  • the invention generally also includes any other marking with alpha, beta or gamma rays.
  • the sequences according to the invention can be linked with any amino acid residues, depending on the use, either chemically or with the help of genetic engineering methods by chemically combining the sequence according to the invention or the heavy or light chains with the molecule to be linked according to generally known methods or be linked by genetic engineering.
  • the sequences according to the invention themselves can also be produced chemically or by genetic engineering.
  • the genes for the heavy chains are lost when the Fc part of the antibody is removed -
  • the passed 3 'regulation sequences stop codon, 3' not to the area and Po I yA Add 11 i onss i gna I) by the C3 exon.
  • the 3 'non-translucent region and the poly-A additio n s i gna I of a human MHC class I gene, preferably an HLA B27 gene, are replaced.
  • the sequence according to the invention can in turn be produced either chemically or by genetic engineering using methods known to those skilled in the art.
  • the DNA sequences which code for the light and heavy chains consist either of genomic sequences or of cDNA sequences or of a mixture of both.
  • the DNA sequences mentioned preferably consist at least partially of genomic DNA.
  • the host cell which is used for the expression of the humMAK described in this invention is a prokaryotic or a eukaryotic cell, in particular Escherichia coli, a yeast such as Saccharomyces or CHO-ZeI - I en.
  • the invention encompasses therapeutic and diagnostic formulations which contain the antibody sequences or sequences or mimetics derived therefrom and their production and the use of such compostments in the therapy and diagnosis of preferably inflammation, solid tumors, in particular breast cancer, gastric cancer, prostate cancer , Lung carcinoma, colon carcinoma, pancreatic carcinoma, Kapos isarcoma etc., as well as non-solid tumors such as leukemia etc.
  • the procedure is, for example, that the covalently bound receptor ligand component I ex as such or in conjunction with an adjuvant for immunization or the complex for immune Selection of V regions of the naive or otherwise generated antibody gene banks.
  • a vertebrate is immunized with the receptor-ligand complex I ex or with the carier-bound receptor-ligand complex in a manner known from later literature, for example by subcutaneous or intaperial injection of the immunogen, if necessary with an adjuvant such as KFA (complete Freund's adjuvant) or IFA (incomplete Freund's adjuvant) or Qu i I A. If necessary, to increase the immune response one or more times " be boosted ".
  • the selection of the species is not critical, for example mice, rats, rabbits, monkeys (Macaca f asc i cu I ar i s), sheep, goats or camels I e are suitable.
  • monoclonal antibodies can of course also be produced. This is done, for example, by immunizing mice, as described above, and then fusion of the mice, for example with NS 1 myeloma cells and cloning of suitable cells. If necessary, the monoclonal antibodies obtained in this way can be multiplied, for example, by injecting the antibody-producing cells into nude mice. In principle, the production of such monoclonal antibodies is known to the person skilled in the art and is described in the literature.
  • mRNA can also be isolated from the malt cells in the unified animal, then produced using reverse transcriptase cDNA and, after amplification if by means of PCR (polymerase chain reaction), cloning takes place of antibody genes in a suitable host.
  • PCR polymerase chain reaction
  • a naive human, murine or primate V library can be prepared from mRNA from peripheral B cells in the phage library system and suitable antibodies can be isolated from it by immunoselection.
  • amp cli cation is preferably cloned into a phage library using PCR.
  • the antibody fragments expressed on the phage surface are selected with the immobilized receptor ligand component I ex. Screening identifies phage clones that recognize the complex immobilized on a solid phase (positive clones). These positive clones are tested in a second screening for binding to the individual components of the complex. Clones that are positive in the 1st screening and negative in the 2nd screening are processed further. Genes of the clones selected in this way are subcloned into suitable vectors and expressed in a suitable host.
  • the invention further relates to antibody (Ak) enzyme fusion proteins, for example Ak-RNase (Saxena, SK et al., J Biol. Chem. 267: 21982-6, 1992), Ak-DNase I (Kreuder V et al. (1984), Eur. J. Biochem. 139, 389-400), Ak-Onconase
  • Activator molecule of coagulation e.g. B. tPA (tissue plas inogen activator) or from Ak and a molecule of the coagulation cascade, for. B. tissue factor (TF) or truncated tissue factor (WO 96/016533, 1994).
  • Another enzyme with a cytotoxic function is recombinant mistletoe lectin (M. Langer et al., 1997. EJC Vol. 33, Suppl. 5, 49).
  • Cell lysis can be achieved by coupling antibodies to e.g. B. Lymphot ⁇ x in (Aggarval et al. (1984) J. Biol. Chem. 259, 686-691) or to a leukalexin (e.g.
  • the antibodies can also be coupled to toxins, e.g. B. the recombinant Pseudomonas exotoxin A (ETA '; Barth et al. 1997. EJC Vol.33. Supp I.5, S22, 39).
  • toxins e.g. B. the recombinant Pseudomonas exotoxin A (ETA '; Barth et al. 1997. EJC Vol.33. Supp I.5, S22, 39).
  • fusion proteins can also be produced by subcloning the scFv in pDN22 (pUC119-Der i vat) via Sf i I and Not l -Rest r i t i onsitte ntte I I en (D. Neri, personal communication).
  • This vector allows the expression of scFv with C-termina-
  • cysteine can be used for chemical
  • the antibodies can be subcloned on the antibody gene in pDN 268 (Neri et al. (1996), Nature Biotechno-
  • the vector pDN268 contains the recognition sequence for the human casein kinase II at the C-terminal as a phosphorization sequence.
  • a variant is the production of scFv with a radioactively markable peptide id. 32 P is used for diagnosis and therapy.
  • linker sequence is the hinge region from the mouse I gG 1 molecule, or homologous human Ig hinge regions, which can be engineered as ant i para II e I peptide sequences.
  • Antibodies can also be produced, for example in single chain diabody format.
  • an antibody fragment with the specificity described above hereinafter referred to as fragment A
  • fragment B an antibody fragment linked to a second antibody fragment (fragment B).
  • the second fragment is specifically directed against a factor from the coagulation cascade (e.g. C1q) or a surface molecule of T cells (CD8, CD24) or TF or TPA or TNF or another effector molecule.
  • the first and second fragments are consecutively called scFv fragments (VH domain with the VL domain of the other fragment, e.g. V H B with V L A and V H A with VB, with a 5 AS long left) a chain is cloned and connected via a 15 AS long left. Expression as a chain results in higher stability and higher yields.
  • VEGF vascular endothelial growth factor
  • VEGF receptor vascular endothelial growth factor
  • mRNA is isolated from the cells of the immunized animals (E. Hornes S. L. Korsnes, 1990, Genet. Anan. Tech. App I.7: 145-150). Subsequently, cDNA is synthesized with the reverse transcriptase (Sambrook, Fritsch, Maniatis 1990; Molecular Cloning, A Laboratory Manual, Second Edition; Cold Spring Harbor Press).
  • Phage that only react with the sFLT-VEGF-Komp I ex is selected by means of immune effect using sFLT-VEGF-Komp I ex immobilized on the solid phase.
  • the phages and / or soluble antibody fragments are tested in an ELISA assay for binding to the immobilized VEGF-sFLT-Komp I ex. Binding antibodies are tested for binding against the receptor (sFLT) or ligand (VEGF) alone. (Phage) antibodies that are negative in the second test are processed further. In the Western blot, these antibodies show no binding to VEGF.sFLT or sKDR alone. The so i mmunse I ect i erten specific
  • Phages are propagated in E.col i by co-infection with the helper phage.
  • the one on the surface of the phage clones expressed scFv are produced by infection of E.col i HB2151 as soluble antibodies.

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

Abstract

L'invention concerne des molécules de fixation contre des complexes récepteur-ligand, qui sont obtenues par immunisation ou immunosélection avec un complexe récepteur-ligand, le récepteur et le ligand étant liés par au moins une liaison covalente, ou bien un, deux ou trois récepteurs identiques ou différents et un, deux ou trois ligands identiques ou différents étant liés les uns aux autres par au moins une liaison covalente. En outre, ces récepteurs sont une protéine ou bien une protéine modifiée par des lipides, du sucre, de l'acide ribonucléique, des phosphates, des protoporphyrines, des flavine-adénine-nucléotides ou bien des métaux, et les ligands sont une protéine, un peptide, un agent de synthèse de faible poids moléculaire, un glycoside ou bien une protéine modifiée par des lipides, du sucre, des acides ribonucléiques, des phosphates, des protoporphyrines, des flavine-adénine-nucléotides ou bien des métaux.
PCT/EP1998/006386 1997-10-09 1998-10-08 Molecules de fixation contre des complexes recepteur-ligand WO1999019361A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU11518/99A AU1151899A (en) 1997-10-09 1998-10-08 Bonding molecules against receptor-ligand-complexes

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19744531.4 1997-10-09
DE1997144531 DE19744531A1 (de) 1997-10-09 1997-10-09 Bindemoleküle gegen Rezeptor-Ligand-Komplexe

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WO1999019361A1 true WO1999019361A1 (fr) 1999-04-22

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WO (1) WO1999019361A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007068895A1 (fr) 2005-12-15 2007-06-21 Astrazeneca Ab Combinaison d'un antagoniste de l'angiopoietine 2 et d'un antagoniste du vegf-a et/ou du kdr et/ou du fltl pour le traitement du cancer

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10016877A1 (de) 2000-04-05 2001-10-18 Scintec Diagnostics Gmbh Zug (Glyko-)Proteine mit hoher Immunreaktivität sowie ein Verfahren zu ihrer Herstellung

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WO1994010202A1 (fr) * 1992-10-28 1994-05-11 Genentech, Inc. Antagonistes du facteur de croissance des cellules endotheliales vasculaires
WO1995015341A1 (fr) * 1993-12-03 1995-06-08 Cancer Research Campaign Technology Limited Anticorps dirige contre l'antigene carcino-embryonnaire (cea)
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US5480792A (en) * 1990-09-14 1996-01-02 Biosite Diagnostics, Inc. Antibodies to complexes of ligand receptors and ligands and their utility in ligand-receptor assays
WO1996030046A1 (fr) * 1995-03-30 1996-10-03 Genentech, Inc. Antagonistes de facteurs de croissance des cellules endotheliales vasculaires
WO1997034634A1 (fr) * 1996-03-20 1997-09-25 Sloan-Kettering Institute For Cancer Research Produits de recombinaison d'anticorps diriges contre le gd2, constitues d'un fragment variable (fv) a chaine simple

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WO1994010202A1 (fr) * 1992-10-28 1994-05-11 Genentech, Inc. Antagonistes du facteur de croissance des cellules endotheliales vasculaires
WO1995015341A1 (fr) * 1993-12-03 1995-06-08 Cancer Research Campaign Technology Limited Anticorps dirige contre l'antigene carcino-embryonnaire (cea)
WO1995025167A1 (fr) * 1994-03-17 1995-09-21 Merck Patent Gmbh Fragments d'anticorps a simple chaine anti-egfr et anticorps anti-egfr
WO1996030046A1 (fr) * 1995-03-30 1996-10-03 Genentech, Inc. Antagonistes de facteurs de croissance des cellules endotheliales vasculaires
WO1997034634A1 (fr) * 1996-03-20 1997-09-25 Sloan-Kettering Institute For Cancer Research Produits de recombinaison d'anticorps diriges contre le gd2, constitues d'un fragment variable (fv) a chaine simple

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007068895A1 (fr) 2005-12-15 2007-06-21 Astrazeneca Ab Combinaison d'un antagoniste de l'angiopoietine 2 et d'un antagoniste du vegf-a et/ou du kdr et/ou du fltl pour le traitement du cancer
EP2518083A2 (fr) 2005-12-15 2012-10-31 Medimmune Limited Combinaison d'un antagoniste de l'angiopoietine 2 et d'un antagoniste du VEGF-A et/ou du KDR et/ou du FLTL pour le traitement du cancer

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AU1151899A (en) 1999-05-03

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