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WO1993015201A1 - Nouvelles tyrosine kinases de proteines - Google Patents

Nouvelles tyrosine kinases de proteines Download PDF

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Publication number
WO1993015201A1
WO1993015201A1 PCT/US1993/000586 US9300586W WO9315201A1 WO 1993015201 A1 WO1993015201 A1 WO 1993015201A1 US 9300586 W US9300586 W US 9300586W WO 9315201 A1 WO9315201 A1 WO 9315201A1
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WIPO (PCT)
Prior art keywords
seq
lptk
bptk
protein
sal
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PCT/US1993/000586
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English (en)
Inventor
Hava Avraham
Jerome Groopman
Sally Cowley
David Scadden
James Mon LEE
Brian Drake Bennett
William I. Wood
David Goeddel
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New England Deaconess Hospital
Genentech, Inc.
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.)
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Publication date
Application filed by New England Deaconess Hospital, Genentech, Inc. filed Critical New England Deaconess Hospital
Priority to EP93903639A priority Critical patent/EP0624192A1/fr
Priority to JP5513345A priority patent/JPH07504813A/ja
Publication of WO1993015201A1 publication Critical patent/WO1993015201A1/fr
Priority to US08/446,648 priority patent/US6331302B1/en
Priority to US09/982,610 priority patent/US6673343B2/en

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/10—Transferases (2.)
    • C12N9/12—Transferases (2.) transferring phosphorus containing groups, e.g. kinases (2.7)
    • C12N9/1205—Phosphotransferases with an alcohol group as acceptor (2.7.1), e.g. protein kinases
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/71—Receptors; Cell surface antigens; Cell surface determinants for growth factors; for growth regulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/82—Translation products from oncogenes
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • Protein tyrosine kinases are enzymes that catalyze this process. Moreover, many act as growth factor receptors.
  • the present invention relates to novel protein tyrosine kinase genes present in human megakaryocytic and lymphocytic cells, the proteins encoded by these genes, antibodies specific for the encoded proteins, RNA nucleic acid sequences which hybridize to the genes and methods of use therefor.
  • pTK protein tyrosine kinase
  • the pTK genes of the present invention show significant sequence homology with members of the c-kit subgroup of growth factor receptors with protein tyrosine kinase activity.
  • the c-kit subgroup of receptor tyrosine kinases catalyze the phosphorylation of exogenous substrates, as well as tyrosine residues within their own polypeptide chains. (Ullrich, A. and Schlessinger, J. , Cell. 61:203 (1990)).
  • Members of the c-kit subgroup include FLT/FLK (Fetal Liver Kinase) , FGF (Fibroblast Growth Factor Receptor) and NGF (Nerve Growth Factor Receptor) .
  • pTK genes fourteen pTK genes have been identified.
  • Two pTK genes referred to as SAL-SI and SAL- D4 (also referred to as megakaryocyte derived FGF-like receptor tyrosine kinase) were identified in megakaryocytic cells.
  • Five pTK genes referred to as LpTKs, were identified in lymphocytic cells and have been shown to be present in megakaryocytes as well.
  • One pTK gene referred to a HpTKs, was identified in human hepatoma cells.
  • Six pTK genes referred to as bpTK genes, found in human brain tissue.
  • SAL-SI is related to the FLT/FLK family of pTKs.
  • SAL-D4 is related to the FGF receptor family of pTKs, and one LpTK (LpTK 3) is related to the NGF receptor family of pTKs.
  • the pTK genes which are the subject of the present invention, were identified using two sets of degenerative oligonucleotide primers: a first set which amplifies all pTK DNA segments (SEQ ID NOS:1-2), and a second set which amplifies highly conserved sequences present in the catalytic domain of the c-kit subgroup of pTKs (SEQ ID NOS:3-4).
  • SAL-SI is expressed in several megakaryocytic cell lines, but not in erythroid cell lines.
  • the nucleotide sequence of SAL-SI was obtained, revealing a sequence containing 158 base pairs. (SEQ ID NO:5).
  • This isolated DNA fragment encoded an amino acid sequence (SEQ ID NO:6) which exhibited significant sequence homology with known protein tyrosine kinases of the FLT/FLK family.
  • the full length gene sequence (SEQ ID NO: 17) contains 6827 b.p. and the deduced amino acid sequence (SEQ ID NO: 18) contains 349 residues.
  • SAL-D4 also expressed in megakaryocytic cells, is a DNA fragment containing the nucleotide sequence of 141 base pairs. (SEQ ID NO:7) . This isolated DNA fragment encoded an amino acid sequence (SEQ ID NO:8) which exhibited significant sequence homology with known protein tyrosine kinases of the FGF receptor family.
  • the LpTKs including LpTK 2, LpTK 3, LpTK 4, and LpTK 13 and LpTK 25, are expressed in lymphocytic cells, as well as megakaryocytic cells.
  • the nucleotide sequence (151 base pairs) of the LpTK 3 gene was obtained (SEQ ID NO:11), and exhibited significant homology with known protein tyrosine kinases of the NGF receptor family.
  • the nucleotide sequences of the LpTK 2, LpTK 4, and LpTK 13 genes contained 149 base pairs (SEQ ID NO:9), 137 base pairs (SEQ ID NO:13), and 211 base pairs (SEQ ID NO:15) respectively.
  • LpTK 25 has a nucleotide sequence of 3120 b.p. (SEQ ID NO: 22) .
  • a full length gene sequence has been obtained for LpTK 2 (SEQ ID NO: 19) which contains 7606 b.p. Additional sequencing of LpTK 4 revealed a sequence of 404 b.p. (SEQ ID NO: 21).
  • the HpTK 5 gene expressed in human hepatoma cells, has a nucleotide sequence of 3120 b.p. (SEQ ID NO: 22) .
  • Nucleotide sequences of the bpTK's are expressed in human brain tissue encode proteins having the amino acid sequences of SEQ ID NOS: 25-30 respectively.
  • the present invention includes DNA isolated from a human megakaryocytic cell line, which hybridizes to a DNA fragment which hybridizes to DNA encoding an amino acid sequence which is highly conserved in the catalytic domain of protein tyrosine kinases of the c-kit subgroup.
  • the present invention also includes the proteins encoded by the pTK genes identified as described herein, which exhibit significant sequence homology with members of the c-kit subgroup of pTks (i.e. FLT/FLK (SAL-SI), FGF receptor (SAL-D4) or NGF receptor (LpTKS) ) as well as the proteins encoded by HpTK 5 and the bpTKs.
  • pTks i.e. FLT/FLK (SAL-SI), FGF receptor (SAL-D4) or NGF receptor (LpTKS)
  • the present invention also includes SAL-SI, SAL-D4, and LpTK, HpTK and bpTK homologues or equivalents (i.e., proteins which have amino acid sequences substantially similar, but not identical, to that of SAL-SI, SAL-D4, the LpTKs HpTK and the bpTKs, which exhibit tyrosine kinase activity.)
  • This invention further includes peptides (SAL-SI, SAL-D4, LpTK, HpTK and bpTK fragments) which retain tyrosine kinase activity, yet are less than the entire SAL-Sl, SAL-D4, LpTK, HpTK and bpTK sequences) , monoclonal and polyclonal antibodies specific for SAL-SI, SAL-D4, the LpTKs, HpTK and the bpTKs, and uses for the SAL-SI, SAL-D4, the LpTK, HpTK and the bpTK
  • the present invention further includes nucleic acid sequences which hybridize with DNA or RNA encoding the proteins described herein, which exhibit significant sequence homology with the FLT/FLK, FGF receptor or NGF receptor family of protein tyrosine kinases contained within the c-kit subgroup.
  • nucleic acid sequences are useful as probes to identify pTK genes in other vertebrates, particularly mammals, and in other cell types. They can also be used as anti-sense oligonucleotides to inhibit protein tyrosine kinase activity, both in vitro and in vivo.
  • the SAL-SI, SAL-D4, LpTK, HpTK and bpTK, tyrosine kinases of the present invention can be used as target proteins in conjunction with the development of drugs and therapeutics to modulate cell growth, differentiation and other metabolic functions.
  • the SAL-SI, SAL-D4, LpTK, HpTK or bpTK proteins can be used as agonists or antagonists to other tyrosine kinases.
  • the SAL-SI, SAL-D4, LpTK, HpTK or bpTK tyrosine kinases can also be instrumental in the modulation of megakaryocyte and/or platelet adhesion interactions.
  • the SAL-SI, SAL-D4, LpTK, HpTK and bpTK tyrosine kinases can be used in screening assays to detect cellular growth and/or differentiation factors.
  • the ligands of the pTKs of the present invention can be identified. Once identified, assays can be designed to detect these ligands present endogenously, within cells, as well as exogenously, in extra cellular fluids. Assays can also be designed as diagnostic aids to detect these ligands in body fluids such as blood and urine.
  • Figure 1 depicts the nucleotide sequence of SAL-SI (SEQ ID NO: 5) and the deduced amino acid sequence (SEQ ID NO:6) .
  • Figure 2 depicts the nucleotide sequence of SAL-D4 (SEQ ID NO:7) and its deduced amino acid sequence (SEQ ID NO:8) .
  • Figure 3A depicts the nucleotide sequence (SEQ ID O:9) and its deduced amino acid sequence (SEQ ID NO:10) for LpTK 2.
  • Figure 3B depicts the nucleotide sequence (SEQ ID O:11) and its deduced amino acid sequence (SEQ ID NO:12) for LpTK 3.
  • Figure 3C depicts the nucleotide sequence (SEQ ID NO:13) and its deduced amino acid sequence (SEQ ID NO:14) for LpTK 4.
  • Figure 3D depicts the nucleotide sequence (SEQ ID NO:15) and its deduced amino acid sequence (SEQ ID NO:16) for the LpTK 13.
  • Figure 4A-4J depicts the full-length nucleotide sequence (SEQ ID NO: 17) and its deduced amino acid sequence (SEQ ID NO: 18) for SAL-SI.
  • Figure 5A-5J depicts the full length nucleotide sequence (SEQ ID NO: 19) and the deduced amino acid sequence (SEQ ID NO: 20) for LpTK2.
  • Figure 6 depicts the partial nucleotide sequence (SEQ ID NO: 21) for LpTK4.
  • Figure 7A-7D depicts the full length nucleotide sequence (SEQ ID NO: 22) for LpTK25.
  • Figure 8A-8F depicts the full length nucleotide sequence (SEQ ID NO: 23) and the deduced amino acid sequence (SEQ ID NO: 24) for HpTK5.
  • Figure 9 depicts the amino acid sequence (SEQ ID NO:
  • Figure 10 depicts the amino acid sequence (SEQ ID NO:
  • Figure 11 depicts the amino acid sequence (SEQ ID NO:
  • Figure 12 depicts the amino acid sequence (SEQ ID NO:
  • Figure 13 depicts the amino acid sequence (SEQ ID NO:
  • Figure 14 depicts the amino acid sequence (SEQ ID NO:
  • Novel protein tyrosine kinase genes have been identified, their nucleic acid sequences determined, and the amino acid sequences of the encoded proteins deduced.
  • the genes isolated as described herein are referred to, collectively, as protein tyrosine kinase (pTK) genes.
  • the nucleic acid sequences of these genes, isolated as discussed herein, show significant homology to with previously identified protein tyrosine kinases containing extracellular domains which function as growth factor receptors. These genes have been shown to be present in both megakaryocytic and lymphocytic cells. To facilitate the isolation and identification of these novel pTKs, two sets of DNA probes were used, as described in the Exemplification.
  • the first set consisted of two degenerative oligonucleotide sequences, pTK 1 (SEQ ID N0:l) and pTK 2 (SEQ ID NO:2) (Matthews, W. Cell 65: 1143 (1991; Wilks, A. F. Proc. Natl. Acad. Sci. USA 86:1603 (1989)). These sequences were used as primers in a polymerase chain reaction to amplify tyrosine kinase DNA segments. (Mullis, K. et al.. Cold Spring Harbor Symp. Advan. Biol. 51:263 (1986).
  • the second set consisted of two oligonucleotide sequences, pTK 3 (SEQ ID NO:3) and pTKK (SEQ ID NO:4) designed to amplify the nucleic acid sequence which encodes the highly conserved regions of the catalytic domains of the c-kit family of protein tyrosine kinases. These sequences were used as primers in the polymerase chain reaction in a second round of DNA amplification. Using this two-step amplification procedure, DNA fragments which hybridized to these pTK primers were identified, isolated and subsequently sequenced.
  • pTK genes exhibiting significant homology with the c-kit subgroup of protein tyrosine kinases have been identified.
  • Two pTK genes referred to as SAL-SI and SAL-D4 (also referred to as megakaryocyte derived FGF-like receptor) were identified in several megakaryocytic cell lines, including CMK 11-5, DAMI, UT-7 and UT-7 grown in erythropoietin, but not in the erythroid cell lines HEL, PMA stimulated HEL cells, or K562.
  • Five pTK genes referred to as LpTKs, were identified in lymphocytic, as well as in megakaryocytic cells.
  • One pTK gene, referred to as HpTK5 was identified in human hepato a cells and six genes, referred to as bpTKs, were identified in human brain tissue.
  • SAL-SI (SEQ ID NO:6 and 18) encoded by the nucleic acid sequence SEQ ID NOS:5 and 17, exhibits significant homology with the FLT/FLK family of pTKs.
  • SAL-D4 (SEQ ID NO:8) encoded by SEQ ID NO:7, is related to the FGF receptor family of pTKs, and one LpTK (LpTK 3 (SEQ ID NO:12) encoded by the SEQ ID NO:11, is related to the NGF receptor family of pTKs.
  • LpTK2 (SEQ ID NO:10) encoded by SEQ ID NO:9
  • LpTK4 (SEQ ID NO:14) encoded by SEQ ID NO:13
  • LpTK13 (SEQ ID NO:16) encoded by SEQ ID NO:15
  • LpTK25 encoded by SEQ ID NO: 22
  • HpTK5 (SEQ ID NO: 24) encoded by SEQ ID NO: 23 and the bpTKs 1, 2, 3, 4, 5 and 7 (SEQ ID NOS: 25-30 respectively, also exhibit sequence homology with known protein tyrosine kinases.
  • DNA which hybridize with DNA encoding amino acid sequences present in the catalytic domain of a protein tyrosine kinase of the c-kit subgroup of protein kinases have been isolated and sequenced.
  • pTKs genes These isolated DNA sequences, collectively referred to as pTKs genes, (and their deduced amino acid sequences) have been shown to exhibit significant sequence homology with known members of receptor tyrosine kinase families.
  • pTKs genes Once isolated, these DNA fragments can be amplified using known standard techniques such as PCR. These amplified fragments can then be cloned into appropriate cloning vectors and their DNA sequences determined.
  • DNA sequences can be excised from the cloning vectors, labeled with a radiolabeled nucleotide such as 32 P and used to screen appropriate cDNA libraries to obtain the full-length cDNA clone.
  • the pTk genes as described above have been isolated from the source in which they occur naturally, i.e. megakaryocyte and lymphocytic cells.
  • the present invention is intended to include pTk genes produced using genetic engineering techniques, such as recombinant technology, as well as pTk genes that are synthesized chemically.
  • the deduced amino acid sequences of the pTK genes include amino acid sequences which encode peptides exhibiting significant homology with the catalytic domain of protein tyrosine kinases of the c-kit subgroup of tyrosine kinases.
  • These proteins, encoded by the pTk genes can include sequences in which functionally equivalent amino acid residues are substituted for residues within the sequence, resulting in a silent change, that is a change not detected phenotypically.
  • one or more amino acid residues within the sequence can be substituted by another amino acid of a similar polarity which acts as a functional equivalent, resulting in a silent substitution.
  • the protein structure can be modified by deletions, additions, inversion, insertions or substitutions of one or more amino acid residues in the sequence which do not substantially detract from the desired functional tyrosine kinases properties of the peptide.
  • Modified pTKs of the present invention, with receptor tyrosine kinase activity can be made using recombinant DNA techniques, such as excising it from a vector containing a cDNA encoding such a protein, or by synthesizing DNA encoding the desired protein mechanically and/or chemically using known techniques.
  • An alternate approach to producing the pTKs of the present invention is to use peptide synthesis to make a peptide or polypeptide having the amino acid sequence of such a protein.
  • the peptides or modified equivalents thereof can be synthesized directly by standard solid or liquid phase chemistries for peptide synthesis.
  • the pTKs of the present invention will be produced by inserting DNA encoding the proteins into an appropriate vector/host system where it will be expressed.
  • the DNA sequences can be obtained from sources in which they occur naturally, can be chemically synthesized or can be produced using standard recombinant technology.
  • This invention also pertains to an expression vector comprising a pTK gene of the present invention, encoding for a protein which exhibits receptor tyrosine kinase activity.
  • the pTK genes of the present invention can be used for a number of diagnostic and therapeutic purposes.
  • the nucleic acid sequences of the pTK genes can be used as probes to identify other protein tyrosine kinases present in other cell types, including eukaryotic and prokaryotic cell types.
  • the nucleic acid sequences can be used to design drugs that directly inhibit the kinase activity of protein tyrosine kinases, or to design peptides that bind to the catalytic domain of tyrosine kinases, thus inhibiting their activity. These sequences can also be used to design anti-sense nucleotides that can also inhibit, or destroy, tyrosine kinase activity. Such inhibition of tyrosine kinase activity would be desirable in pathological states where decreased cellular proliferation would be beneficial, such as leukemias or other malignancies.
  • nucleic acid sequences can also be used to design drugs, peptides or anti-sense nucleotides as above, but with enhancing, rather than inhibitory effects, on tyrosine kinases.
  • Such enhanced tyrosine kinase activity would result in increasing the phosphorylation of substrates (exogenous, as ⁇ well as endogenous tyrosine residues) .
  • Enhanced effects would be desirable in states where increased cellular proliferation would be beneficial, such as anemias, bleeding disorders and during surgical procedures.
  • the pTK genes of the present invention can also be used to obtain soluble fragments of receptor tyrosine kinases, capable of binding their respective ligands (i.e. fibroblast growth factor) .
  • pTK genes encoding soluble receptor tyrosine kinase fragments can be produced using recombinant DNA techniques or synthetically. In either case, the DNA obtained encodes a soluble pTK fragment which lacks a substantial portion of the hydrophobic transmembrane region to permit solubilization of the fragment.
  • soluble pTK protein fragments can be introduced exogenously to act as competitors with the endogenous, membrane bound pTK for their respective ligands, thus inhibiting tyrosine kinase activity.
  • a modified soluble pTK protein fragment can be introduced which binds the ligand but does not activate kinase activity.
  • soluble pTK protein fragments can also be used in binding assays to detect ligands such as growth and differentiation factors. Once these ligands are identified, they may be altered or modified to inhibit or enhance kinase activity. For example, the ligands may be modified or attached to substances that are toxic to the cell, such a ricin, thus destroying the target cell. The substance may be a super-activating substance which, after binding to the pTK, may substantially increase the kinase activity, or activate other growth factors.
  • pTk genes of the present invention would also be useful to develop diagnostic tools for in vitro screening assays for ligands such as growth factors or differentiation factors that inhibit or enhance kinase activity.
  • the proteins encoded by the pTK genes can also be used in such assays, or as immunogens to produce monoclonal or polyclonal antibodies to be used in such assays.
  • Such antibodies can also be used in methods of treating conditions in which an individual would benefit therapeutically if protein tyrosine kinase activity could be modified, such as increasing platelet production in bleeding disorders.
  • the first set consisted of two degenerative oligonucleotide sequences, pTK 1 (SEQ ID N0:1) and pTK 2(SEQ ID NO:2). These sequences were used as polymerase chain reaction (PCR) primers, using standard PCR techniques, to amplify tyrosine kinase DNA segments.
  • the second set consisted of two oligonucleotide sequences, pTK 3 (SEQ ID NO:3) and pTKKW (SEQ ID NO:4) selected from the highly conserved regions of the catalytic domains of the c-kit subgroup of protein tyrosine kinases. These sequences were also used as polymerase chain reaction primers in a second round of DNA amplification. Using this two-step amplification procedure, DNA fragments which hybridized to these pTK primers were identified, isolated and subsequently sequenced using known laboratory techniques.

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Abstract

L'invention se rapporte à l'identification et à l'isolation de nouvelles tyrosine kinases de protéines présentes en tant que gènes sur des cellules mégakaryocytiques et lymphocytiques humaines, aux protéines codées par ces gènes, à des anticorps spécifiques de ces protéines codées, à des séquences d'acides nucléiques ARN qui s'hybrident avec ces gènes et à des procédés d'utilisation correspondants.
PCT/US1993/000586 1992-01-22 1993-01-22 Nouvelles tyrosine kinases de proteines WO1993015201A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP93903639A EP0624192A1 (fr) 1992-01-22 1993-01-22 Nouvelles tyrosine kinases de proteines
JP5513345A JPH07504813A (ja) 1992-01-22 1993-01-22 新規蛋白質チロシンキナーゼ類
US08/446,648 US6331302B1 (en) 1992-01-22 1995-04-04 Protein tyrosine kinase agonist antibodies
US09/982,610 US6673343B2 (en) 1992-01-22 2001-10-17 SAL-S1 receptor protein tyrosine kinase agonist antibodies

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US82693592A 1992-01-22 1992-01-22
US826,935 1992-01-22

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US6887674B1 (en) 1998-04-13 2005-05-03 California Institute Of Technology Artery- and vein-specific proteins and uses therefor
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US8444957B2 (en) 1998-10-09 2013-05-21 Vegenics Pty Limited Methods of screening for neoplastic disease states
US8940695B2 (en) 2001-01-19 2015-01-27 Vegenics Pty Limited Flt4 (VEGFR-3) as a target for tumor imaging and anti-tumor therapy
US8975377B2 (en) 2007-08-13 2015-03-10 Vasgene Therapeutics, Inc Cancer treatment using humanized antibodies that bind to EphB4
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US11672803B2 (en) 2010-06-03 2023-06-13 Pharmacyclics Llc Use of inhibitors of Brutons tyrosine kinase (Btk)

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