JPH07504813A - Novel protein tyrosine kinases - Google Patents
Novel protein tyrosine kinasesInfo
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- JPH07504813A JPH07504813A JP5513345A JP51334593A JPH07504813A JP H07504813 A JPH07504813 A JP H07504813A JP 5513345 A JP5513345 A JP 5513345A JP 51334593 A JP51334593 A JP 51334593A JP H07504813 A JPH07504813 A JP H07504813A
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- 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
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- 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
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Abstract
(57)【要約】本公報は電子出願前の出願データであるため要約のデータは記録されません。 (57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.
Description
【発明の詳細な説明】 新規蛋白質チロシンキナーゼ類 発明の背景 細胞の増殖および分化を調節するシグナルの伝達は、部分的に、種々の細胞蛋白 質のホスホリル化によって調節されている。蛋白質チロシンキーナーゼ類はこの ような過程を触媒する酵素である。更に、それらの多くは成長因子レセプタとし て働く。[Detailed description of the invention] Novel protein tyrosine kinases Background of the invention The transmission of signals that regulate cell proliferation and differentiation depends, in part, on the transmission of signals that regulate cell proliferation and differentiation. regulated by quality phosphorylation. Protein tyrosine keyases are It is an enzyme that catalyzes such a process. Furthermore, many of them act as growth factor receptors. work.
発明の要約 本発明は、ヒト巨核球およびリンパ球細胞内に存在している新規な蛋白質チロシ ンキナーゼ遺伝子、これらの遺伝子がコード化する蛋白質、これらのコード化さ れた蛋白質に特異的な抗体、これらの遺伝子にハイブリッド形成するＲＮＡ核酸 配列、並びにそれらの使用方法に関する。Summary of the invention The present invention provides novel protein tyrosinase present in human megakaryocytes and lymphocytes. Kinase genes, the proteins these genes encode, and the proteins these encode. antibodies that are specific to the proteins identified, RNA nucleic acids that hybridize to these genes. Concerning arrays and how to use them.
本明細書に記述する如く単離した遺伝子を、集合的に、蛋白質チロシンキナーゼ （ｐＴＫ）遺伝子と呼ぶ。本明細書に考察する如く単離した上記遺伝子の核酸配 列は、成長因子レセプタとして機能する細胞外ドメインを含んでいる、既に同定 されている蛋白質チロシンキナーゼ類に有意な相同性を示す。これらのｐＴＫ遺 伝子は目積球およびリンパ球両方の細胞内に存在していることが示された。Genes isolated as described herein collectively represent protein tyrosine kinases. (pTK) gene. The nucleic acid sequences of the genes isolated as discussed herein The previously identified column contains an extracellular domain that functions as a growth factor receptor. Shows significant homology to protein tyrosine kinases. These pTK genes The gene was shown to be present in both phthalmocytes and lymphocytes.
本発明のｐＴＫ遺伝子は、蛋白質チロシンキナーゼ活性を示すＣ−キラ）（ｃ− ｋｉｔ）サブグループの成長因子レセプタ類の一員に有意な配列相同性を示す。The pTK gene of the present invention exhibits protein tyrosine kinase activity (C-chira) (c- kit) exhibits significant sequence homology to members of the subgroup growth factor receptors.
このＣ−キットサブグループのレセプタチロシンキナ（Ｕｌ ｌ ｒ ｉｃｈ、 Ａ、およびＳｃｈｌｅｓｓｉｎｇｅｒ、Ｊ、 、Ｃｅ１１．６１ ： ２０３ （１９９０）。このＣ−キットサブグループの一員には、ＦＬＴ／ＦＬＫ （ 胎児肝臓キナーゼ） 、ＦＧＦ （線維芽細胞成長因子レセプタ）およびＮＧＦ （神経成長因子レセプタ）が含まれる。This C-kit subgroup receptor tyrosinquina (Ullrich, A., and Schlessinger, J., Ce11.61: 203 (1990). Members of this C-kit subgroup include FLT/FLK ( Fetal liver kinase), FGF (fibroblast growth factor receptor) and NGF (Nerve growth factor receptor) is included.
特に、１４種のｐＴＫ遺伝子を同定した。５ＡＬ−３１および５ＡＬ−Ｄ４と呼 ぶ２種のｐＴＫ遺伝子（また、目積球由来ＦＧＦ様レセプタチロシンキナーゼと も呼ぶ）を目積球細胞内で同定した。ＬｐＴＫ類と呼ぶ５種のｐＴＫ遺伝子をリ ンパ球細胞内で同定し、そしてこれらは同様に目積球内にも存在していることが 示された。ＨｐＴＫと呼ぶ１種のｐＴＫ遺伝子をヒト肝癌細胞内で同定した。ｂ ｐＴＫ遺伝子と呼ぶ６種のｐＴＫ遺伝子がヒト脳組織内で見付かった。In particular, 14 types of pTK genes were identified. Called 5AL-31 and 5AL-D4 pTK genes of two species (also FGF-like receptor tyrosine kinase derived from ocular bulbs) ) was identified in the eyeball cells. Five types of pTK genes, called LpTKs, have been extracted. identified within lymphocytic cells, and they were found to be present within ocular spheres as well. Shown. One pTK gene, termed HpTK, was identified in human hepatoma cells. b Six types of pTK genes, referred to as pTK genes, have been found in human brain tissue.
５ＡＬ−３１はＦＬＴ／ＦＬＫ系群（ファミリー）のｐＴＫに関係している。５ ＡＬ−Ｄ４はＦＧＦレセプタ系群（ファミリー）のｐＴＫに関係しており、そし て１種のＬｐＴＫ （ＬｐＴＫ３）はＮＧＦレセプタ系群（ファミリー）のｐＴ Ｋに関係している。5AL-31 is related to pTKs of the FLT/FLK family. 5 AL-D4 is related to the FGF receptor family pTK and One type of LpTK (LpTK3) is the pT of the NGF receptor family. It is related to K.
２組の変性オリゴヌクレオチドプライマーを用いて本発明の主題であるｐＴＫ遺 伝子を同定したが、その１番目の組は、全てのｐＴＫ ＤＮＡ配列（配列同定番 号：１−２）を増幅するものであり、そして２番目の組は、Ｃ−キットサブグル ープのｐＴＫの触媒ドメイン内に存在している高度に保存されている配列（配列 同定番号： ３−４）を増幅するものである。このようにして同定したｐ Ｔ Ｋ遺伝子を以下に記述する。The pTK gene, which is the subject of the present invention, was prepared using two sets of degenerated oligonucleotide primers. The first set contains all pTK DNA sequences (sequence identity standard). No. 1-2), and the second set amplifies the C-Kit subgroup. A highly conserved sequence within the catalytic domain of pTK (sequence Identification number: 3-4). pT identified in this way The K gene is described below.
５ＡＬ−３１は、いくつかの目積球細胞系内で発現するが、赤芽球細認された。5AL-31 is expressed in some ocular cell lines but was found in erythroblasts.
この単離したＤＮＡフラグメントは、ＦＬＴ／ＦＬＫ系群（ファミリー）の公知 蛋白質チロシンキナーゼ類に有意な配列相同性を示すアミノ酸配列（配列同定番 号；６）をコードしていた。この全長遺伝子配列（配列同定番号：１７）は、６ ８２７個の塩基対（ｂ、ｐ、 ）を含んでおり、そしてその推定アミノ酸配列（ 配列同定番号＝１８）は３４９個の残基を含んでいる。This isolated DNA fragment is a known member of the FLT/FLK family. Amino acid sequences showing significant sequence homology to protein tyrosine kinases (sequence identity standard) No. 6) was coded. This full-length gene sequence (sequence identification number: 17) is 6 It contains 827 base pairs (b, p, ) and its deduced amino acid sequence ( Sequence ID number = 18) contains 349 residues.
目積球細胞内でも発現する５ＡＬ−Ｄ４は、１４１個の塩基対から成るヌクレオ チド配列を含んでいるＤＮＡフラグメントである（配列同定番号ニア）。この単 離したＤＮＡフラグメントは、ＦＧＦレセプタ系群（ファミリー）の公知蛋白質 チロシンキナーゼに有意な配列相同性を示すアミノ酸配列（配列同定番号：８） をコード化した。5AL-D4, which is also expressed in ocular cells, is a nucleoprotein consisting of 141 base pairs. This is a DNA fragment containing the sequence (sequence identification number near). This single The separated DNA fragment is a known protein of the FGF receptor family. Amino acid sequence showing significant sequence homology to tyrosine kinase (Sequence identification number: 8) was coded.
ＬｐＴＫ２、ＬｐＴＫ３、ＬｐＴＫ４およびＬｐＴＫ１３およびｔ、ｐＴＫ２５ を含むＬｐＴＫ類は、リンパ球細胞内で発現すると共に目積球細胞内で発現する 。このＬｐＴＫ３遺伝子のヌクレオチド配列（１５１個の塩基対）を入手しく配 列同定番号：１１）、そしてこれはＮＧＦレセプタ系群（ファミリー）の公知蛋 白質チロシンキナーゼ類に有意な相同性を示した。これらのＬｐＴＫ２、ＬｐＴ Ｋ４およびＬｐＴＫ１３遺伝子のヌクレオチド配列は、それぞれ１４９個の塩基 対（配列同定番号＋９）、１３７個の塩基対（配列同定番号：１３）および２１ １個の塩基対（配列同定番号：１５）を含んでいた。ＬｐＴＫ２５は３１２０個 の塩基対から成るヌクレオチド配列を有している（配列同定番号：２２）。７６ ０６個の塩基対を含んでいるＬｐＴＫ２ （配列同定番号：１９）号：２１）。LpTK2, LpTK3, LpTK4 and LpTK13 and t, pTK25 LpTKs, including . The nucleotide sequence (151 base pairs) of this LpTK3 gene was obtained and arranged in the correct manner. sequence identification number: 11), and this is a known protein of the NGF receptor family. It showed significant homology to white matter tyrosine kinases. These LpTK2, LpT The nucleotide sequences of the K4 and LpTK13 genes are 149 bases each. pair (SEQ ID NO: +9), 137 base pairs (SEQ ID NO: 13) and 21 It contained one base pair (sequence identification number: 15). LpTK25 is 3120 pieces It has a nucleotide sequence consisting of base pairs (sequence identification number: 22). 76 LpTK2 (Sequence Identification Number: 19) No.: 21) containing 06 base pairs.
ヒト肝癌細胞内で発現するＨ ｐ Ｔ Ｋ ５遺伝子は、３１２０個の塩基対か ら成るヌクレオチド配列を有している（配列同定番号＝２２）。ｂｐＴＫＩ、ｂ ｐＴＫ２、ｂｐＴＫ３、ｂｐＴＫ４、ｂｐＴＫ５およびｂｐＴＫ７を含むｂｐＴ Ｋ類のヌクレオチド配列は、ヒト脳組織内で発現し、そしてそれぞれ配列同定番 号： ２５−３０のアミノ酸配列を有する蛋白質をコード化する。The HpTK5 gene expressed in human liver cancer cells has a length of 3120 base pairs. It has a nucleotide sequence consisting of (sequence identification number = 22). bpTKI,b bpT including pTK2, bpTK3, bpTK4, bpTK5 and bpTK7 The K nucleotide sequences are expressed in human brain tissue and each has a sequence identity. No.: Encodes a protein with an amino acid sequence of 25-30.
従って、本発明は、ヒト巨核球細胞系から単離したＤＮＡを包含しており、これ は、Ｃ−キットサブグループの蛋白質チロシンキナーゼ類の触媒ドメイン内の高 度に保存されているアミノ酸配列をコード化するＤＮＡにハイブリッド形成する ＤＮＡフラグメントにハイブリッド形成する。Accordingly, the present invention encompasses DNA isolated from human megakaryocytic cell lines; is a highly concentrated protein in the catalytic domain of protein tyrosine kinases of the C-kit subgroup. hybridizes to DNA encoding a conserved amino acid sequence Hybridize to DNA fragments.
本発明はまた、Ｃ−キットサブグループのｐＴＫ類の一員（即ちＦＬＴ／ＦＬＫ （ＳＡＬ−３１） 、ＦＧＦレセプタ（ＳＡＬ−Ｄ４）またはＮＧＦレセプタ （ＬｐＴＫ類））に有意な配列相同性を示す、本明細書に記述する如く同定した ｐＴＫ遺伝子がコード化する蛋白質、並びに■４ｐＴＫ５およびｂｐＴＫ類がコ ード化する蛋白質も包含している。本発明はまた、５ＡＬ−３１，５ＡＬ−Ｄ４ 、並びにＬｐＴＫ、ＨｐＴＫおよびｂｐＴＫ同族体または相当物（即ちチロシン キナーゼ活性を示す、５ＡＬ−Ｓｌ、５ＡＬ−Ｄ４、ＬｐＴＫ類、ＨｐＴＫおよ びｂｐＴＫ類のそれと本質的に同様なアミノ酸配列を有しているがそれとは同じ でなおよびｂｐＴＫ配列よりも短いペプチド類（ＳＡＬ−８ｔ、５ＡＬ−Ｄ４、 ＬｐＴＫ、ＨｐＴＫおよびｂｐＴＫフラグメント） 、５ＡＬ−３ｌ、５ＡＬ− ０４、ＬｐＴＫ類、Ｉ−Ｉ ｐ Ｔ ＫおよびｂｐＴＫ類に特異的なモノクロー ナルおよびポリクローナル抗体、並びに５ＡＬ−８ｔ、５ＡＬ−Ｄ４、ＬｐＴＫ 類、ＨｐＴＫおよびｂｐＴＫ類の核酸配列そして５ＡＬ−３Ｌ、５ＡＬ−Ｄ４、 ＬｐＴＫ、ＨｐＴＫおよびｂｐＴＫ相当物の使用も包含している。The present invention also relates to members of the pTK family of the C-kit subgroup (i.e., FLT/FLK (SAL-31), FGF receptor (SAL-D4) or NGF receptor (LpTKs)), identified as described herein, show significant sequence homology to The protein encoded by the pTK gene, and ■4pTK5 and bpTKs are It also includes proteins that are coded. The present invention also provides 5AL-31, 5AL-D4 , and LpTK, HpTK and bpTK homologs or equivalents (i.e. tyrosine 5AL-Sl, 5AL-D4, LpTKs, HpTK and It has essentially the same amino acid sequence as that of the bpTKs; and peptides shorter than the bpTK sequence (SAL-8t, 5AL-D4, LpTK, HpTK and bpTK fragments), 5AL-3l, 5AL- 04, monochrome specific for LpTKs, I-I pTKs and bpTKs null and polyclonal antibodies, and 5AL-8t, 5AL-D4, LpTK the nucleic acid sequences of HpTK and bpTK, and 5AL-3L, 5AL-D4, Also included is the use of LpTK, HpTK and bpTK equivalents.
本発明は更に、Ｃ−キットサブグループ内に含まれているＦＬＴ／ＦＬＫ、ＦＧ ＦレセプタまたはＮＧＦレセプタ系群（ｆａａ＋１ｌｙ）の蛋白質チロシンキナ ーゼ類に有意な配列相同性を示す、本明細書に記述する蛋白質をコード化するＤ ＮＡまたはＲＮＡにハイブリッド形成する核酸配列も包含している。上記核酸配 列は、他のを推動物、特に哺乳動物および池の細胞型内に存在しているｐＴＫ遺 伝子を同定するためのプローブとして有効性を示す。これらはまた、インビトロ およびインビボ両方において、蛋白質チロシンキナーゼ活性を阻害するアンチセ ンスオリゴヌクレオチド類として用いられ得る。The present invention further provides FLT/FLK, FG, which are included within the C-kit subgroup. Protein tyrosinequina of the F receptor or NGF receptor family (faa+1ly) D encoding the proteins described herein that exhibit significant sequence homology to Also included are nucleic acid sequences that hybridize to NA or RNA. The above nucleic acid sequence The pTK gene is present in other mammalian cells, especially mammals and cell types. Demonstrates effectiveness as a probe for gene identification. These can also be used in vitro. antiserum that inhibits protein tyrosine kinase activity both in vivo and in vivo. can be used as oligonucleotides.
本発明の５ＡＬ−８１，５ＡＬ−Ｄ４、ＬｐＴＫ、ＨｐＴＫおよびｂｐＴＫチロ シンキナーゼ類は、細胞の増殖、分化および他の代謝機能を調節する薬剤および 治療剤の開発に関連して標的蛋白質として用いられ得る。これらの５ＡＬ−５１ ，５ＡＬ−Ｄ４、ＬｐＴＫ、ＨｐＴＫまたはｂｐＴＫ蛋白質は、池のチロシンキ ナーゼ類に対する作動薬または拮抗薬として用いられ得る。これらの５ＡＬ−８ １、Ｓ Ａ Ｌ −Ｄ ４、ｉ、ｐＴＫＳＨｐＴＫまたはｂｐＴＫチロシンキナ ーゼ類はまた、目積球およ化因子を検出するスクリーニングアッセイで用いられ 得る。標準的実験室技術を用いて、本発明のｐＴＫ類のりカントを同定すること ができる。5AL-81, 5AL-D4, LpTK, HpTK and bpTK tiro of the present invention Synkinases are drugs and drugs that regulate cell proliferation, differentiation, and other metabolic functions. It can be used as a target protein in connection with the development of therapeutic agents. These 5AL-51 , 5AL-D4, LpTK, HpTK or bpTK protein is a pond tyrosine protein. It can be used as an agonist or antagonist for enzymes. These 5AL-8 1, S AL - D 4, i, pTKSHpTK or bpTK tyrosine kina enzymes are also used in screening assays to detect ectophores and factors. obtain. Identifying the pTKs of the invention using standard laboratory techniques Can be done.
同定した後、細胞内に内因的に存在している上記リガンド、並びに細胞外液内に 外因的に存在している上記リガンドを検出するアッセイを設計することができる 。血液および尿の如き体液内に存在している上記リガンドを検出する診断補助と してまたアッセイを設計することができる。After identification, the above-mentioned ligands exist endogenously in the cell as well as in the extracellular fluid. Assays can be designed to detect the above-mentioned ligands when they are exogenously present. . A diagnostic aid for detecting the above-mentioned ligands in body fluids such as blood and urine. and assays can also be designed.
図の簡単な説明 図１は、５ＡＬ−５Ｌのヌクレオチド配列（配列同定番号・５）およびそれの推 定アミノ酸配列（配列同定番号＝６）を表している。Brief description of the diagram Figure 1 shows the nucleotide sequence of 5AL-5L (sequence identification number: 5) and its prediction. It represents a constant amino acid sequence (sequence identification number=6).
図２は、ＳＡＬ−０４のヌクレオチド配列（配列同定番号、７）およびそれの推 定アミノ酸配列（配列同定番号：８）を表している。Figure 2 shows the nucleotide sequence of SAL-04 (sequence identification number, 7) and its derivation. It represents a constant amino acid sequence (sequence identification number: 8).
図３Ａは、ＬｐＴＫ２に関するヌクレオチド配列（配列同定番号：９）およびそ れの推定アミノ酸配列（配列同定番号、１０）を表している。Figure 3A shows the nucleotide sequence for LpTK2 (SEQ ID NO: 9) and its The deduced amino acid sequence (sequence identification number: 10) is shown.
図３Ｂは、ＬｐＴＫ３に関するヌクレオチド配列（配列同定番号：１１）および それの推定アミノ酸配列（配列同定番号：１２）を表している。Figure 3B shows the nucleotide sequence for LpTK3 (SEQ ID NO: 11) and Its deduced amino acid sequence (sequence identification number: 12) is shown.
図３０は、ＬｐＴＫ４に関するヌクレオチド配列（配列同定番号：１３）および それの推定アミノ酸配列（配列同定番号：１４）を表している。Figure 30 shows the nucleotide sequence for LpTK4 (sequence identification number: 13) and Its deduced amino acid sequence (sequence identification number: 14) is shown.
図３Ｄは、ＬｐＴＫ１３に関するヌクレオチド配列（配列同定番号：いる。Figure 3D shows the nucleotide sequence for LpTK13 (Sequence ID number:
図４Ａ−４Ｊは、５ＡＬ−３１に関する全長ヌクレオチド配列（配列同定番号＝ １７）およびそれの推定アミノ酸配列（配列同定番号：１８）を表している。Figures 4A-4J show the full-length nucleotide sequence for 5AL-31 (sequence identification number = 17) and its deduced amino acid sequence (sequence identification number: 18).
図５Ａ−５Ｊは、ＬｐＴＫ２に関する全長ヌクレオチド配列（配列同定番号 １ ９）および推定アミノ酸配列（配列同定番号＝２０）を表している。Figures 5A-5J show the full-length nucleotide sequence for LpTK2 (sequence identification number 1 9) and the deduced amino acid sequence (sequence identification number=20).
図６は、ＬｐＴＫ４に関する部分ヌクレオチド配列（配列同定番号：２１）を表 している。Figure 6 shows the partial nucleotide sequence (sequence identification number: 21) regarding LpTK4. are doing.
図７Ａ−７Ｄは、ＬｐＴＫ２５に関する全長ヌクレオチド配列（配列同定番号： ２２）を表している。Figures 7A-7D show the full-length nucleotide sequence for LpTK25 (Sequence identification number: 22).
図８Ａ−８Ｆは、ＩＩｐＴＫ５に関する全長ヌクレオチド配列（配列同定番号： ２３）および推定アミノ酸配列（配列同定番号：２４）を表している。Figures 8A-8F show the full-length nucleotide sequence for IIpTK5 (Sequence Identification Number: 23) and the deduced amino acid sequence (sequence identification number: 24).
図９は、ｂｐＴＫｌのアミノ酸配列（配列同定番号＝２５）を表している。FIG. 9 shows the amino acid sequence of bpTKl (sequence identification number=25).
図１０は、ｂｐＴＫ２のアミノ酸配列（配列同定番号：２６）を表している。FIG. 10 shows the amino acid sequence of bpTK2 (Sequence ID number: 26).
図１１は、ｂｐＴＫ３のアミノ酸配列（配列同定番号、２７）を表している。FIG. 11 shows the amino acid sequence of bpTK3 (sequence identification number, 27).
図１２は、ｂｐＴＫ４のアミノ酸配列（配列同定番号：２８）を表している。FIG. 12 shows the amino acid sequence of bpTK4 (Sequence ID number: 28).
図１３は、ｂｐＴＫ５のアミノ酸配列（配列同定番号、２９）を表し新規な蛋白 質チロシンキナーゼ遺伝子を同定し、それらの核酸配列を決定し、そしてそのコ ード化した蛋白質のアミノ酸配列を推定した。本明細書に記述する如く単離した 遺伝子を、集合的に、蛋白質チロシンキナーゼ（ｐＴＫ）遺伝子と呼ぶ。本明細 書で考察する如く単離した上記遺伝子の核酸配列は、成長因子レセプタとして機 能する細胞外ドメインを含んでいる、以前に同定した蛋白質チロシンキナーゼ類 に有意な相同性を示す。これらの遺伝子は目積球およびリンパ球両方の細胞内に 存在していることが示された。Figure 13 shows the amino acid sequence of bpTK5 (sequence identification number: 29), which is a novel protein. identified tyrosine kinase genes, determined their nucleic acid sequences, and The amino acid sequence of the coded protein was deduced. isolated as described herein. The genes are collectively referred to as protein tyrosine kinase (pTK) genes. Specification The nucleic acid sequence of the above gene, isolated as discussed in the book, has been shown to function as a growth factor receptor. Previously identified protein tyrosine kinases that contain an extracellular domain capable of shows significant homology. These genes are found in both ocular cells and lymphocytes. was shown to exist.
これらの新規ｐＴＫ類の単離および同定を容易にする目的で、実施例の中に記述 する如き２組のＤＮＡプローブを用いた。その１番目の組は、２種の変性オリゴ ヌクレオチド配列ｐＴＫ１ （配列同定番号＝１）およびｐＴＫ２ （配列同定 番号：２）から成っていた（Ｍａｔｔｈｅｗｓ。To facilitate the isolation and identification of these novel pTKs, the Two sets of DNA probes were used. The first set consists of two modified oligos. Nucleotide sequences pTK1 (sequence identification number = 1) and pTK2 (sequence identification Number: 2) (Matthews.
Ｗ、、Ｃｅｌ １ ６５．：１１４３ （１９９１）；Ｗｉ ｌｋｓ、Ａ、Ｆ、 、Ｐｒｏｃ、Ｎａｔｌ、Ａｃａｄ、Ｓｃｉ、ＵＳＡ ８６：１６０３ （１９８ ９））。これらの配列をポリメラーゼ連鎖反応のプライマーとして用いてチロシ ンキナーゼのＤＮＡセグメントの増幅を行った（Ｍｕｌｌｉｓ、に他、Ｃｏ１ｄ Ｓｐｒｉｎｇ Ｈａｒｂｏｒ Ｓｙｍｐ、Ａｄｖａｎ、 Ｂｉｏｌ、 、５１ ：２６３ （１９８６）。W,, Cel 1 65. :1143 (1991); Wilks, A.F. , Proc, Natl, Acad, Sci, USA 86:1603 (198 9)). These sequences were used as primers for polymerase chain reaction to generate tyrosinease. Amplification of the DNA segment of the protein kinase was carried out (Mullis, et al., Col. Spring Harbor Symp, Advan, Biol, 51 :263 (1986).
２番目の組は、Ｃ−キット系群（ファミリー）の蛋白質チロシンキナーゼ類が有 する触媒ドメインの高度に保存されている領域をコード化すから成っていた。こ れらの配列を第二ラウンドのＤＮＡ増幅におけるポリメラーゼ連鎖反応のプライ マーとして用いた。このような２段階の増幅操作を用いて、上記ｐＴＫプライマ ー類にハイブリッド形成するＤＮＡフラグメントを同定し、単離した後、配列決 定を行つた。The second set includes the C-Kit family of protein tyrosine kinases. It consisted of a highly conserved region encoding a catalytic domain. child These sequences were used as polymerase chain reaction primers in the second round of DNA amplification. It was used as a marker. Using such a two-step amplification operation, the above pTK primer After identifying and isolating DNA fragments that hybridize to I made a decision.
特に、Ｃ−キットサブグループの蛋白質チロシンキナーゼ類に有意な相同性を示 す１４種のｐＴＫ遺伝子を同定した。５ＡＬ−８１および５ＡＬ−Ｄ４と呼ぶ２ 種のｐＴＫ遺伝子（また、目積球由来ＦＧＦ様レセプタとも呼ぶ）を、ＣＭＫＩ Ｉ−５、ＤＡＭＩ、ＵＴ−７、およびエリトロポイエチン内で増殖するＵＴ−７ を含むいくつかの目積球細胞系内で同定したが、赤芽球細胞系１１ＥＬ、ＰＭＡ 刺激ＨＥＬ細胞またはに５６２内では同定されなかった。ＬｐＴＫ類と呼ぶ５種 のｐＴＫ遺伝子を、リンパ球細胞内で同定すると共に目積球内でも同定した。Ｈ ｐＴＫ５と呼ぶ１種のｐＴＫ遺伝子をヒト肝癌細胞内で同定し、そしてｂｐＴＫ 類と呼ぶ６種のｐＴＫ遺伝子をヒト脳組織内で同定した。In particular, it shows significant homology to protein tyrosine kinases of the C-kit subgroup. We identified 14 types of pTK genes. 2 referred to as 5AL-81 and 5AL-D4 The species pTK gene (also called phthalmosphere-derived FGF-like receptor) is expressed by CMKI UT-7 growing in I-5, DAMI, UT-7, and erythropoietin The erythroid cell line 11EL, PMA No stimulated HEL cells or cells were identified within 562. Five types called LpTKs The pTK gene was identified in lymphoid cells as well as in ocular bulbs. H One pTK gene, termed pTK5, was identified in human hepatoma cells and bpTK We identified six pTK genes in human brain tissue.
核酸配列同定番号５および１７がコード化する５ＡＬ−３Ｌ （配列同定番号＝ ６および１８）は、ＦＬＴ／ＦＬＫ系群（ファミリー）のｐＴＫ類に有意な相同 性を示す。配列同定番号＝７がコード化する５ＡＬ−Ｄ４（配列同定番号：８） は、ＦＧＦレセプタ系群（ファミリー）のｐＴＫ類に関係しており、そして配列 同定番号：１１がコード化する１種のＬｐＴＫ （ＬｐＴＫ３ （配列同定番号 ：１２））は、ＮＧＦレセプタ系群（ファミリー）のｐＴＫ類に関係してる。そ の残りのＬｐＴＫ類であるところの、配列同定番号＝９がコード化するＬｐＴＫ ２ （配列同定列同定番号二１６）、配列同定番号＝２２がコード化するＬｐＴ Ｋ２５もまた、公知蛋白質チロシンキナーゼ類に配列相同性を示す（データは示 していない）。5AL-3L encoded by nucleic acid sequence identification numbers 5 and 17 (sequence identification number = 6 and 18) have significant homology to pTKs of the FLT/FLK family. Show your gender. 5AL-D4 encoded by sequence identification number = 7 (sequence identification number: 8) are related to the pTKs of the FGF receptor family, and the sequence Identification number: 11 encodes one type of LpTK (LpTK3 (sequence identification number :12)) are related to the pTKs of the NGF receptor family. So Of the remaining LpTKs, LpTK encoded by sequence identification number = 9 2 (sequence identification sequence identification number 216), LpT encoded by sequence identification number = 22 K25 also shows sequence homology to known protein tyrosine kinases (data not shown). (Not done).
配列同定番号＝２３がコード化する）（ｐＴＫ５ （配列同定番号：２４）およ びｂｐＴＫ類１．２．３．４．５および７（配列同定番号＝２５−３０）もまた 、それぞれ公知蛋白質チロシンキナーゼ類に配列相同性を示す。Sequence identification number = 23 encodes) (pTK5 (sequence identification number: 24) and and bpTKs 1.2.3.4.5 and 7 (sequence identification numbers = 25-30) are also , each exhibiting sequence homology to known protein tyrosine kinases.
従って、上述したように、Ｃ−キットサブグループの蛋白質チロシンキナーゼ類 の蛋白質チロシンキナーゼの触媒ドメイン内に存在しているアミノ酸配列をコー ド化するＤＮＡにハイブリッド形成するＤＮＡを単離し、そして配列決定を行っ た。ｐＴＫ遺伝子と集合的に呼ぶこれらの単離したＤＮＡ配列（並びにそれらの 推定アミノ酸配列）は、レセプタチロシンキナーゼ系群（ファミリー）の公知− 員に有意な配列相同性をホすることが示された。Therefore, as mentioned above, protein tyrosine kinases of the C-kit subgroup encodes the amino acid sequence present in the catalytic domain of the protein tyrosine kinase of The DNA that hybridizes to the DNA to be coded is isolated and sequenced. Ta. These isolated DNA sequences (as well as their Deduced amino acid sequence) is a known receptor tyrosine kinase family. It was shown that there is significant sequence homology between the members.
単離した後、ＰＣＲの如き公知標準技術を用いてこれらのＤＮＡフラグメントの 増幅を行うことができる。次に、これらの増幅させたフラグメントを適当なりロ ーニングベクターにクローン化して、それらのＤＮＡ配列を決定することができ る。After isolation, these DNA fragments are analyzed using standard techniques known in the art such as PCR. Amplification can be performed. Next, place these amplified fragments in a suitable location. vectors and their DNA sequences can be determined. Ru.
これらのクローニングベクターからＤＮＡ配列を切除し、３２ｐの如き放射能標 識ヌクレオチドで標識した後、これらを用いて適当なｃ ＤＮＡライブラリーを スクリーニングすることによって、全長ｃＤＮＡクローンを得ることができる。Excise the DNA sequence from these cloning vectors and add a radiolabel such as 32p. After labeling with identifying nucleotides, use these to create an appropriate cDNA library. By screening, full-length cDNA clones can be obtained.
例えば組換え技術などを用いて作り出したｐ Ｔ Ｋ遺伝子、並びに化学的に合 成したｐＴＫ遺伝子も包含することを意図している。For example, the pTK gene created using recombinant technology, as well as chemically synthesized It is also intended to include the pTK gene that has been constructed.
これらのｐＴＫ遺伝子の推定アミノ酸配列には、Ｃ−キットサブグループのチロ シンキナーゼ類の蛋白質チロシンキナーゼ類の触媒ドメインに有意な相同性を示 すペプチド類をコード化するアミノ酸配列が含まれる。これらのｐＴＫ遺伝子が コード化するこれらの蛋白質には、サイレント変化をもたらす、即ち変化が表現 型的に検出されないところの、その配列内の残基を機能的に相当するアミノ酸残 基で置換した配列が含まれ得る。例えば、その配列内に存在している１個以上の アミノ酸残基を、機能相当物として働く同様な極性を示す別のアミノ酸で置換す る結果として、サイレント置換をもたらすことができる。The deduced amino acid sequences of these pTK genes include tyrosine of the C-kit subgroup. Shows significant homology to the catalytic domain of protein tyrosine kinases. Contains amino acid sequences encoding peptides. These pTK genes These encode proteins that result in silent changes, i.e. changes that are not expressed Functionally equivalent amino acid residues for residues in the sequence that are not typically detected Sequences substituted with groups may be included. For example, one or more items present in the array Substitution of an amino acid residue with another amino acid of similar polarity that acts as a functional equivalent can result in a silent substitution.
加うるに、そのペプチドに所望の機能的チロシンキナーゼ特性を有意に損わせる ことのない、その配列内に存在している１個以上のアミノ酸残基に関する欠失、 付加、転置、挿入または置換を行うことによって、その蛋白質構造の修飾を行う ことができる。In addition, it significantly impairs the desired functional tyrosine kinase properties of the peptide. deletion of one or more amino acid residues that are present in the sequence, Modify the protein structure by making additions, transpositions, insertions, or substitutions be able to.
組換えＤＮＡ技術、例えば上記蛋白質をコード化するｃＤＮＡ含有ベクターから の切除によるか、或は所望蛋白質をコード化するＤＮＡを公知技術により機械的 および／または化学的に合成することによって、レセプタチロシンキナーゼ活性 を示す本発明の修飾ｐＴＫ類を作り出すことができる。Recombinant DNA techniques, e.g. from cDNA-containing vectors encoding the above proteins. or by mechanically cutting the DNA encoding the desired protein using known techniques. and/or by chemically synthesizing receptor tyrosine kinase activity. Modified pTKs of the invention can be created that exhibit:
本発明のｐＴＫ類を作り出す代替アプローチは、ペプチド合成を用いて上記蛋白 質のアミノ酸配列を有するペプチドまたはポリペプチドを作好適には、蛋白質を コード化するＤＮＡを、それを発現する適当なべフタ−／宿主系に挿入すること によって、本発明のｐＴＫ類を作り出す。An alternative approach to creating the pTKs of the invention is to use peptide synthesis to Preferably, the protein is Inserting the encoding DNA into a suitable vector/host system in which it will be expressed. The pTKs of the present invention are produced by:
これらのＤＮＡ配列は、それらが天然に存在している給源から入手可能であるか 、或は化学合成することが可能であるか、或は標準的組換え技術を用いてそれら を作り出すことができる。Are these DNA sequences available from their naturally occurring sources? , or can be chemically synthesized or produced using standard recombinant techniques. can be produced.
本発明はまた、レセプタチロシンキナーゼ活性を示す蛋白質の遺伝情報を指定す る本発明のｐＴＫ遺伝子を含んでいる発現ベクターにも関する。The present invention also specifies genetic information for proteins exhibiting receptor tyrosine kinase activity. It also relates to an expression vector containing the pTK gene of the present invention.
本発明のｐＴＫ遺伝子は数多くの診断および治療目的で用いられ得る。The pTK gene of the invention can be used for numerous diagnostic and therapeutic purposes.
例えば、これらのｐＴＫ遺伝子の核酸配列をプローブとして用いて、真核細胞お よび原核細胞型を含む他の細胞型内に存在している他の蛋白質チロシンキナーゼ 類を同定することができる。For example, using the nucleic acid sequences of these pTK genes as probes, eukaryotic cells and and other protein tyrosine kinases present in other cell types, including prokaryotic cell types. The class can be identified.
蛋白質チロシンキナーゼ類が示すキナーゼ活性を直接阻害する薬剤を設計するか 、或はチロシンキナーゼ類の触媒ドメインに結合してそれらの活性を阻害するペ プチド類を設計する目的で、これらの核酸配列を用いることができる。これらの 配列はまた、チロシンキナーゼ活性をまた阻害し得るか或は壊し得るアンチセン スヌクレオチド類を設計する目的で用いられ得る。このようなチロシンキナーゼ 活性の阻害は、細胞増殖を低下させることが有利である病理状態、例えば白血病 または他の悪性疾患において望ましいものである。Should we design drugs that directly inhibit the kinase activity of protein tyrosine kinases? , or a compound that binds to the catalytic domain of tyrosine kinases and inhibits their activity. These nucleic acid sequences can be used to design peptides. these The sequence may also contain antisense compounds that may also inhibit or destroy tyrosine kinase activity. can be used for the purpose of designing nucleotides. Such tyrosine kinases Inhibition of activity is useful in pathological conditions where it is advantageous to reduce cell proliferation, e.g. leukemia. or desirable in other malignant diseases.
これらの核酸配列はまた、上述した如き薬剤、ペプチド類またはアンチロジンキ ナーゼ類に対して阻害効果を示すのではなくむしろ増強する。These nucleic acid sequences may also be used as drugs, peptides or antirodin molecules as described above. It does not have an inhibitory effect on enzymes, but rather enhances them.
このようにチロシンキナーゼ活性が増強されると、基質（外因性、並びに内因性 チロメン残基）のホスホリル化の増強がもたらされる。細胞増殖を上昇させるこ とが有利である状態、例えば貧血、出血疾患および外科操作中などでは、その効 果を上昇させる方が望ましい。When tyrosine kinase activity is enhanced in this way, substrates (exogenous as well as endogenous This results in enhanced phosphorylation of thyromene residues). Increases cell proliferation Its effectiveness may be reduced in conditions where it is advantageous, such as anemia, bleeding disorders and during surgical operations. It is preferable to raise the fruit.
本発明のｐＴＫ遺伝子はまた、個々のリガンド（即ち線維芽細胞成長因子）に結 合し得るレセプタチロシンキナーゼ類の可溶フラグメントを得る目的で用いられ 得る。The pTK genes of the invention also bind to individual ligands (i.e. fibroblast growth factors). used to obtain soluble fragments of receptor tyrosine kinases that can be obtain.
組換えＤＮＡ技術を用いるか或は合成的に、可溶レセプタチロシンキナーゼフラ グメントをコード化するｐＴＫ遺伝子を作り出すことができる。両方の場合共、 その得られるＤＮＡは、疎水性トランスメンブラン領域の実質的部分が欠如して いてそのフラグメントの可溶化を可能にする可溶ｐＴＫフラグメントをコード化 する。Soluble receptor tyrosine kinase fractions can be produced using recombinant DNA technology or synthetically. A pTK gene can be created that encodes a component. In both cases, The resulting DNA lacks a substantial portion of the hydrophobic transmembrane region. encodes a soluble pTK fragment that allows for solubilization of the fragment do.
これらの可溶ｐＴＫ蛋白質フラグメントを外因的に導入することにより、内因性 膜結合ｐＴＫの競合相手（それらの個々のりガントに関する）として働かせるこ とによって、チロシンキナーゼ活性を阻害することができる。また、リガンドに 結合するがキナーゼ活性を活性化しないように修飾した可溶ｐＴＫ蛋白質フラグ メントを導入することができる。By exogenously introducing these soluble pTK protein fragments, endogenous act as competitors (with respect to their individual glues) of membrane-bound pTKs. Tyrosine kinase activity can be inhibited by Also, the ligand Soluble pTK protein flag modified to bind but not activate kinase activity can be introduced.
これらの可溶ｐＴＫ蛋白質フラグメントはまた、成長因子および分化因子の如き リガンドを検出する結合アッセイで用いられ得る。これらのりガントを同定した 後、キナーゼ活性を阻害するか或は増強する目的でこれらを変化させるか或はそ れらの修飾を行うことができる。例えば、これらのりガントの修飾を行うか、或 は細胞に毒性を示す物質、例えばこのｐＴＫにｎした後そのキナーゼ活性を本質 的に増大させ得るか或は他の成長因子を活性化し得る、超活性化物質であっても よい。These soluble pTK protein fragments also contain molecules such as growth and differentiation factors. Can be used in binding assays to detect ligands. These glue gunts were identified. Afterwards, these changes are made for the purpose of inhibiting or enhancing the kinase activity, or These modifications can be made. For example, modify these glue gants or is a substance that is toxic to cells, such as pTK. Even if it is a superactivator that can increase growth factors or activate other growth factors. good.
本発明のｐＴＫ遺伝子はまた、キナーゼ活性を阻害もしくは増強する成長因子ま たは分化因子の如きリガンドをインビトロでスクリーニングするアッセイのため の診断道具を開発する目的で用いられるであろう。The pTK gene of the present invention may also contain growth factors that inhibit or enhance kinase activity. or for in vitro screening assays for ligands such as differentiation factors. It will be used for the purpose of developing diagnostic tools.
これらのｐＴＫ遺伝子がコード化する蛋白質はまた、上記アッセイで用いられ得 るか、或は上記アッセイで用いるべきモノクローナルもしくはポリクローナル抗 体を生じさせるための免疫原として用いられ得る。The proteins encoded by these pTK genes can also be used in the above assays. monoclonal or polyclonal antibodies to be used in the above assays. It can be used as an immunogen to raise the body.
上記抗体はまた、もし蛋白質チロシンキナーゼ活性を修飾することができたなら ば個体が治療学的利点を得るであろう状態を治療する方法、例えば出血疾患にお いて血小板産生を増加させる方法で用いられ得る。The above antibodies could also be used if they were able to modify protein tyrosine kinase activity. A method of treating a condition for which an individual would derive therapeutic benefit, such as a bleeding disorder. can be used in a method to increase platelet production.
如何なる様式でも限定することを意図したものでない下記の実施例を用いて、本 発明をここに説明する。The present invention is illustrated by way of example, which is not intended to be limiting in any way. The invention will now be described.
実施例：ｐＴＫ遺伝子の同定および単離これらの新規ｐＴＫ遺伝子の単離および 同定を容易にする目的で、２組のＤＮＡプローブを用いた（表参照）。Example: Identification and isolation of pTK genes Isolation and isolation of these novel pTK genes Two sets of DNA probes were used to facilitate identification (see table).
その１番目の組は、２種の変性オリゴヌクレオチド配列ｐＴＫ１ （配列同定番 号、１）およびｐＴＫ２（配列同定番号：２）から成っていた。The first set consists of two types of degenerated oligonucleotide sequences pTK1 (sequence identity standard). No. 1) and pTK2 (sequence identification number: 2).
標準的ポリメラーゼ連鎖反応（ＰＣＲ）を用い、これらの配列をＰＣＲプライマ ーとして用いてチロシンキナーゼのＤＮＡセグメントの増幅を行った。Using standard polymerase chain reaction (PCR), these sequences are combined with PCR primers. The DNA segment of tyrosine kinase was amplified using the following method.
２番目の組は、Ｃ−キット系群（ファミリー）の蛋白質チロシンキナーゼ類の触 媒ドメインの高度に保存されている領域から選択した２種のＷ（配列前窓番号＝ ４）から成っていた。また、これらの配列を第二ラウンドのＤＮＡ増幅における ポリメラーゼ連鎖反応のプライマーとして用いた。公知実験室技術を用い、この ような２段階の増幅操作を用いて、これらのｐＴＫプライマー類にハイブリッド 形成するＤＮＡフラグメントを同定し、単離した後、配列決定を行ったＴＫＩ ＣＧＧＡＴＣＣＡＣＡＧＮＧＡＣＣＴ ＴＫ２ ＧＧ＾＾ＴＴＣＣ＾＾＾ＧＧＡＣＣＡＧＡＣＧＴＣ第二ラウンドの増幅 ＰＴＫ３ （キット系群（ファミリー）特異的）ＣＧＧＡＴＣＣＡＴＣＣＡＣＡ ＧＡＧＡＴＧＴＰＴＫＫｆ （キット系群（ファミリー）特異的）ＧＧＡＡＴＴ ＣＣＴＴＣＡＧＧＡＧＣＣ八ＴＣＣＡＣＴＴ相当物 本分野の技術へは、本明細書に記述した本発明の特定具体例に対する数多くの相 当物を、常規のみの実験を用いて認識するか或は確かめることができるであろう 。このような相当物を下記の請求の範囲内に包含させることを意図している。The second set consists of the C-Kit family of protein tyrosine kinases. Two types of W selected from highly conserved regions of the medial domain (sequence front window number = 4). In addition, these sequences were used in the second round of DNA amplification. It was used as a primer for polymerase chain reaction. Using known laboratory techniques, this These pTK primers were hybridized using a two-step amplification procedure such as The DNA fragments formed by TKIs were identified, isolated, and then sequenced. CGGATCCACAGNGACCT TK2 GG^^TTCC^^^GGACCAGACGTC second round amplification PTK3 (Kit family specific) CGGATCCATCCACA GAGATGTPTKKf (Kit family specific) GGAATT CCTTCAGGAGCC8TCCACTT equivalent There are many variations to the art to the specific embodiments of the invention described herein. The object may be recognized or ascertained using only routine experimentation. . It is intended that such equivalents be included within the scope of the following claims.
息Ｊ ち−ｍ υ ＬｐＴＩＣ２ ＬｐＴＫコ ＧＴＧＣＡＣＡＧＧＧ入ＴＣＴＣＧＣＧＧＣＴＣＧＧ入ＡＣｋＴＣＣＴＣＩ：Ｔ ＣＧＧＧＧ入入ＡＪＩＣＡＣＣＣＴＣＴＣＧｋｋＡＣＴＴＡＴＣＣＣＣＴＡ（Ａ ＡＡＴＧＧＡＴＧＧＣＣＣＣＴＧＡＣＧＧ入ＡｐＴＫ４ ＡＣＡＣ入入入ＴＣＡＣＴＧＣＣＧＣ ＬｐτＸ］コ ＴＸＧＶｐ、Ｅ コｐ 補正書の写しく翻訳文）提出書 （特許法第１８４条の８）平成６年７月２１日Breath J chi-m υ LpTIC2 LpTK Ko GTGCACAGGG input TCTCGCGGCTCGGG input ACkTCCTCI:T CGGGG entry AJICACCCTCTCGkkACTTATCCCCCTA (A ApTK4 with AATGGATGGCCCCTGACGG ACAC admissionTCACTGCCGC LpτX]ko TXGVp, E Cop Copy and translation of amendment) Submission (Article 184-8 of the Patent Law) July 21, 1994
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Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
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| US82693592A | 1992-01-22 | 1992-01-22 | |
| US826,935 | 1992-01-22 | ||
| PCT/US1993/000586 WO1993015201A1 (en) | 1992-01-22 | 1993-01-22 | Novel protein tyrosine kinases |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH07504813A true JPH07504813A (en) | 1995-06-01 |
Family
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| JP5513345A Pending JPH07504813A (en) | 1992-01-22 | 1993-01-22 | Novel protein tyrosine kinases |
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| Country | Link |
|---|---|
| EP (1) | EP0624192A1 (en) |
| JP (1) | JPH07504813A (en) |
| AU (1) | AU3482493A (en) |
| CA (1) | CA2128722A1 (en) |
| WO (1) | WO1993015201A1 (en) |
Families Citing this family (35)
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| US5728536A (en) * | 1993-07-29 | 1998-03-17 | St. Jude Children's Research Hospital | Jak kinases and regulation of Cytokine signal transduction |
| US6331302B1 (en) | 1992-01-22 | 2001-12-18 | Genentech, Inc. | Protein tyrosine kinase agonist antibodies |
| US5635177A (en) * | 1992-01-22 | 1997-06-03 | Genentech, Inc. | Protein tyrosine kinase agonist antibodies |
| US6824777B1 (en) | 1992-10-09 | 2004-11-30 | Licentia Ltd. | Flt4 (VEGFR-3) as a target for tumor imaging and anti-tumor therapy |
| US6107046A (en) * | 1992-10-09 | 2000-08-22 | Orion Corporation | Antibodies to Flt4, a receptor tyrosine kinase and uses thereof |
| EP0732398B1 (en) * | 1993-08-25 | 2004-07-14 | Asahi Kasei Kabushiki Kaisha | Novel tyrosine kinase |
| US6652850B1 (en) | 1993-09-13 | 2003-11-25 | Aventis Pharmaceuticals Inc. | Adeno-associated viral liposomes and their use in transfecting dendritic cells to stimulate specific immunity |
| US5834441A (en) * | 1993-09-13 | 1998-11-10 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Adeno-associated viral (AAV) liposomes and methods related thereto |
| EP0730740B1 (en) * | 1993-11-23 | 1998-02-11 | Genentech, Inc. | Kinase receptor activation assay |
| US6001621A (en) * | 1993-11-23 | 1999-12-14 | Genetech, Inc. | Protein tyrosine kinases |
| AU697142B2 (en) | 1993-11-23 | 1998-10-01 | Genentech Inc. | Protein tyrosine kinases named Rse |
| US6287784B1 (en) | 1993-11-23 | 2001-09-11 | Genentech, Inc. | Kinase receptor activation assay |
| AU1120895A (en) * | 1993-12-02 | 1995-06-19 | Asahi Kasei Kogyo Kabushiki Kaisha | Novel receptor tyrosine kinase |
| US6506578B1 (en) | 1994-04-22 | 2003-01-14 | Sugen, Inc. | Nucelotide encoding megakaryocytic protein tyrosine kinases |
| US6326469B1 (en) | 1994-04-22 | 2001-12-04 | Sugen, Inc. | Megakaryocytic protein tyrosine kinases |
| GB9410534D0 (en) * | 1994-05-26 | 1994-07-13 | Lynxvale Ltd | Improvements in or relating to growth factor inhibitors |
| US5864020A (en) * | 1994-07-20 | 1999-01-26 | Genentech, Inc. | HTK ligand |
| WO1996026958A2 (en) * | 1995-02-27 | 1996-09-06 | President And Fellows Of Harvard College | Eph RECEPTOR LIGAND ELF-2 |
| US6531296B1 (en) * | 1995-06-20 | 2003-03-11 | The University Of North Carolina At Chapel Hill | Nuclear tyrosine kinase Rak |
| DE69628652T3 (en) | 1995-09-08 | 2012-05-03 | Genentech, Inc. | VEGF-RELATED PROTEIN |
| US5981201A (en) | 1997-01-08 | 1999-11-09 | Beth Israel Deaconess Medical Center | Methods of detection and treatment of breast cancer |
| US6864227B1 (en) | 1998-04-13 | 2005-03-08 | California Institute Of Technology | Artery-and vein-specific proteins and uses therefor |
| US6887674B1 (en) | 1998-04-13 | 2005-05-03 | California Institute Of Technology | Artery- and vein-specific proteins and uses therefor |
| US6811992B1 (en) | 1998-05-14 | 2004-11-02 | Ya Fang Liu | Method for identifying MLK inhibitors for the treatment of neurological conditions |
| ES2357406T3 (en) | 1998-10-09 | 2011-04-26 | Vegenics Limited | Flt4 (VEGFR-3) AS A DIANA FOR OBTAINING IMAGES OF TUMORS AND ANTITUMORAL THERAPY. |
| JP4669984B2 (en) | 2001-01-19 | 2011-04-13 | ベジェニクス リミテッド | F1t4 (VEGFR-3) and antitumor therapy as a target for tumor imaging |
| US7381410B2 (en) | 2003-03-12 | 2008-06-03 | Vasgene Therapeutics, Inc. | Polypeptide compounds for inhibiting angiogenesis and tumor growth |
| CA2518912A1 (en) | 2003-03-12 | 2004-09-23 | Vasgene Therapeutics, Inc. | Polypeptide compounds for inhibiting angiogenesis and tumor growth |
| JP2007508801A (en) * | 2003-10-24 | 2007-04-12 | エスバテック・アーゲー | Methods for identification and / or confirmation of receptor tyrosine kinase inhibitors |
| DK1730196T3 (en) | 2004-03-12 | 2011-03-28 | Vasgene Therapeutics Inc | EphB4-binding antibodies to inhibit antiogenesis and tumor growth |
| AU2005224081B2 (en) | 2004-03-12 | 2011-06-30 | Vasgene Therapeutics, Inc. | Polypeptide compounds for inhibiting angiogenesis and tumor growth |
| WO2006034455A2 (en) | 2004-09-23 | 2006-03-30 | Vasgene Therapeutics, Inc. | Polipeptide compounds for inhibiting angiogenesis and tumor growth |
| WO2009023185A1 (en) | 2007-08-13 | 2009-02-19 | Vasgene Therapeutics, Inc. | Cancer treatment using humanized antibodies that bind to ephb4 |
| WO2011153514A2 (en) | 2010-06-03 | 2011-12-08 | Pharmacyclics, Inc. | The use of inhibitors of bruton's tyrosine kinase (btk) |
| JP6408492B2 (en) | 2013-02-18 | 2018-10-17 | ヴェジェニクス プロプライエタリー リミテッドＶｅｇｅｎｉｃｓ Ｐｔｙ Ｌｉｍｉｔｅｄ | Ligand binding molecules and uses thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE221915T1 (en) * | 1991-02-22 | 2002-08-15 | American Cyanamid Co | IDENTIFICATION OF A HUMAN RECEPTOR TYROSINE KINASE GENE |
-
1993
- 1993-01-22 AU AU34824/93A patent/AU3482493A/en not_active Abandoned
- 1993-01-22 CA CA 2128722 patent/CA2128722A1/en not_active Abandoned
- 1993-01-22 WO PCT/US1993/000586 patent/WO1993015201A1/en not_active Application Discontinuation
- 1993-01-22 JP JP5513345A patent/JPH07504813A/en active Pending
- 1993-01-22 EP EP93903639A patent/EP0624192A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| WO1993015201A1 (en) | 1993-08-05 |
| EP0624192A1 (en) | 1994-11-17 |
| CA2128722A1 (en) | 1993-08-05 |
| AU3482493A (en) | 1993-09-01 |
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