US2007010442A1PendingUtilityA1
Inhibitor of vascular endothelial cell growth factor
Individually held — no corporate assignee on recordPriority: Mar 25, 1993Filed: Mar 14, 2006Published: Jan 11, 2007
Est. expiryMar 25, 2013(expired)· nominal 20-yr term from priority
C07K 14/715A61K 38/00A61P 9/00A61P 43/00C07K 14/71
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Claims
Abstract
The vascular endothelial cell growth factor (VEGF) inhibitors of the present invention are naturally occurring or recombinantly engineered soluble forms with or without a C-terminal transmembrane region of the receptor for VEGF, a very selective growth factor for endothelial cells. The soluble forms of the receptors will bind the growth factor with high affinity but do not result in signal transduction. These soluble forms of the receptor bind VEGF and inhibit its function.
Claims
exact text as granted — not AI-modified1 . A soluble VEGF inhibitor in substantially pure form which specifically binds VEGF and inhibits cellular VEGF receptor activity.
2 . The soluble VEGF inhibitor according to claim 1 wherein the soluble VEGF receptor is selected from the group consisting of sVEGF-RI, sVEGF-RII, sVEGF-RTMI and sVEGF-RTMII.
3 . The soluble VEGF inhibitor of claim 2 corresponding to sVEGF-RI comprising the amino acid sequence:
Met Val Ser Tyr Trp Asp Thr Gly
(SEQ. ID. NO.:6)
Val Leu Leu Cys Ala Leu Leu Ser
Cys Leu Leu Leu Thr Gly Ser Ser
Ser Gly Ser Lys Leu Lys Asp Pro
Glu Leu Ser Leu Lys Gly Thr Gln
His Ile Met Gln Ala Gly Gln Thr
Leu His Leu Gln Cys Arg Gly Glu
Ala Ala His Lys Trp Ser Leu Pro
Glu Met Val Ser Lys Glu Ser Glu
Arg Leu Ser Ile Thr Lys Ser Ala
Cys Gly Arg Asn Gly Lys Gln Phe
Cys Ser Thr Leu Thr Leu Asn Thr
Ala Gln Ala Asn His Thr Gly Phe
Tyr Ser Cys Lys Tyr Leu Ala Val
Pro Thr Ser Lys Lys Lys Glu Thr
Glu Ser Ala Ile Tyr Ile Phe Ile
Ser Asp Thr Gly Arg Pro Phe Val
Glu Met Tyr Ser Glu Ile Pro Glu
Ile Ile His Met Thr Glu Gly Arg
Glu Leu Val Ile Pro Cys Arg Val
Thr Ser Pro Asn Ile Thr Val Thr
Leu Lys Lys Phe Pro Leu Asp Thr
Leu Ile Pro Asp Gly Lys Arg Ile
Ile Trp Asp Ser Arg Lys Gly Phe
Ile Ile Ser Asn Ala Thr Tyr Lys
Glu Ile Gly Leu Leu Thr Cys Glu
Ala Thr Val Asn Gly His Leu Tyr
Lys Thr Asn Tyr Leu Thr His Arg
Gln Thr Asn Thr Ile Ile Asp Val
Gln Ile Ser Thr Pro Arg Pro Val
Lys Leu Leu Arg Gly His Thr Leu
Val Leu Asn Cys Thr Ala Thr Thr
Pro Leu Asn Thr Arg Val Gln Met
Thr Trp Ser Tyr Pro Asp Glu Lys
Asn Lys Arg Ala Ser Val Arg Arg
Arg Ile Asp Gln Ser Asn Ser His
Ala Asn Ile Phe Tyr Ser Val Leu
Thr Ile Asp Lys Met Gln Asn Lys
Asp Lys Gly Leu Tyr Thr Cys Arg
Val Arg Ser Gly Pro Ser Phe Lys
Ser Val Asn Thr Ser Val His Ile
Tyr Asp Lys Ala Phe Ile Thr Val
Lys His Arg Lys Gln Gln Val Leu
Glu Thr Val Ala Gly Lys Arg Ser
Tyr Arg Leu Ser Met Lys Val Lys
Ala Phe Pro Ser Pro Glu Val Val
Trp Leu Lys Asp Gly Leu Pro Ala
Thr Glu Lys Ser Ala Arg Tyr Leu
Thr Arg Gly Tyr Ser Leu Ile Ile
Lys Asp Val Thr Glu Glu Asp Ala
Gly Asn Tyr Thr Ile Leu Leu Ser
Ile Lys Gln Ser Asn Val Phe Lys
Asn Leu Thr Ala Thr Leu Ile Val
Asn Val Lys Pro Gln Ile Tyr Glu
Lys Ala Val Ser Ser Phe Pro Asp
Pro Ala Leu Tyr Pro Leu Gly Ser
Arg Gln Ile Leu Thr Cys Thr Ala
Tyr Gly Ile Pro Gln Pro Thr Ile
Lys Trp Phe Trp His Pro Cys Asn
His Asn His Ser Glu Ala Arg Cys
Asp Phe Cys Ser Asn Asn Glu Glu
Ser Phe Ile Leu Asp Ala Asp Ser
Asn Met Gly Asn Arg Ile Glu Ser
Ile Thr Gln Arg Met Ala Ile Ile
Glu Gly Lys Asn Lys Met Ala Ser
Thr Leu Val Val Ala Asp Ser Arg
Ile Ser Gly Ile Tyr Ile Cys Ile
Ala Ser Asn Lys Val Gly Thr Val
Gly Arg Asn Ile Ser Phe Tyr Ile
Thr Asp Val Pro Asn Gly Phe His
Val Asn Leu Glu Lys Met Pro Thr
Glu Gly Glu Asp Leu Lys Leu Ser
Cys Thr Val Asn Lys Phe Leu Tyr
Arg Asp Val Thr Trp Ile Leu Leu
Arg Thr Val Asn Asn Arg Thr Met
His Tyr Ser Ile Ser Lys Gln Lys
Met Ala Ile Thr Lys Glu His Ser
Ile Thr Leu Asn Leu Thr Ile Met
Asn Val Ser Leu Gln Asp Ser Gly
Thr Tyr Ala Cys Arg Ala Arg Asn
Val Tyr Thr Gly Glu Glu Ile Leu
Gln Lys Lys Glu Ile Thr Ile Arg
Gly Glu His Cys Asn Lys Lys Ala
Val Phe Ser Arg Ile Ser Lys Phe
Lys Ser Thr Arg Asn Asp Cys Thr
Thr Gln Ser Asn Val Lys His.
4 . The soluble VEGF inhibitor of claim 2 corresponding to sVEGF-RI comprising the amino acid sequence:
Ser Lys Leu Lys Asp Pro Glu Leu
(SEQ. ID. NO.:12)
Ser Leu Lys Gly Thr Gln His Ile
Met Gln Ala Gly Gln Thr Leu His
Leu Gln Cys Arg Gly Glu Ala Ala
His Lys Trp Ser Leu Pro Glu Met
Val Ser Lys Glu Ser Glu Arg Leu
Ser Ile Thr Lys Ser Ala Cys Gly
Arg Asn Gly Lys Gln Phe Cys Ser
Thr Leu Thr Leu Asn Thr Ala Gln
Ala Asn His Thr Gly Phe Tyr Ser
Cys Lys Tyr Leu Ala Val Pro Thr
Ser Lys Lys Lys Glu Thr Glu Ser
Ala Ile Tyr Ile Phe Ile Ser Asp
Thr Gly Arg Pro Phe Val Glu Met
Tyr Ser Glu Ile Pro Glu Ile Ile
His Met Thr Glu Gly Arg Glu Leu
Val Ile Pro Cys Arg Val Thr Ser
Pro Asn Ile Thr Val Thr Leu Lys
Lys Phe Pro Leu Asp Thr Leu Ile
Pro Asp Gly Lys Arg Ile Ile Trp
Asp Ser Arg Lys Gly Phe Ile Ile
Ser Asn Ala Thr Tyr Lys Glu Ile
Gly Leu Leu Thr Cys Glu Ala Thr
Val Asn Gly His Leu Tyr Lys Thr
Asn Tyr Leu Thr His Arg Gln Thr
Asn Thr Ile Ile Asp Val Gln Ile
Ser Thr Pro Arg Pro Val Lys Leu
Leu Arg Gly His Thr Leu Val Leu
Asn Cys Thr Ala Thr Thr Pro Leu
Asn Thr Arg Val Gln Met Thr Trp
Ser Tyr Pro Asp Glu Lys Asn Lys
Arg Ala Ser Val Arg Arg Arg Ile
Asp Gln Ser Asn Ser His Ala Asn
Ile Phe Tyr Ser Val Leu Thr Ile
Asp Lys Met Gln Asn Lys Asp Lys
Gly Leu Tyr Thr Cys Arg Val Arg
Set Gly Pro Ser Phe Lys Ser Val
Asn Thr Set Val His Ile Tyr Asp
Lys Ala Phe Ile Thr Val Lys His
Arg Lys Gln Gln Val Leu Glu Thr
Val Ala Gly Lys Arg Ser Tyr Arg
Leu Ser Met Lys Val Lys Ala Phe
Pro Ser Pro Glu Val Val Trp Leu
Lys Asp Gly Leu Pro Ala Thr Glu
Lys Ser Ala Arg Tyr Leu Thr Arg
Gly Tyr Ser Leu Ile Ile Lys Asp
Val Thr Glu Glu Asp Ala Gly Asn
Tyr Thr Ile Leu Leu Set Ile Lys
Gln Ser Asn Val Phe Lys Asn Leu
Thr Ala Thr Leu Ile Val Asn Val
Lys Pro Gln Ile Tyr Glu Lys Ala
Val Ser Ser Phe Pro Asp Pro Ala
Leu Tyr Pro Leu Gly Ser Atg Gln
Ile Leu Thr Cys Thr Ala Tyr Gly
Ile Pro Gln Pro Thr Ile Lys Trp
Phe Trp His Pro Cys Asn His Asn
His Ser Glu Ala Arg Cys Asp Phe
Cys Ser Asn Asn Glu Glu Ser Phe
Ile Leu Asp Ala Asp Ser Asn Met
Gly Asn Arg Ile Glu Ser Ile Thr
Gln Atg Met Ala Ile Ile Glu Gly
Lys Asn Lys Met Ala Ser Thr Leu
Val Val Ala Asp Ser Arg Ile Ser
Gly Ile Tyr Ile Cys Ile Ala Ser
Asn Lys Val Gly Thr Val Gly Arg
Asn Ile Ser Phe Tyr Ile Thr Asp
Val Pro Asn Gly Phe His Val Asn
Leu Glu Lys Met Pro Thr Glu Gly
Glu Asp Leu Lys Leu Ser Cys Thr
Val Asn Lys Phe Leu Tyr Arg Asp
Val Thr Trp Ile Leu Leu Arg Thr
Val Asn Asn Arg Thr Met His Tyr
Ser Ile Ser Lys Gln Lys Met Ala
Ile Thr Lys Glu His Set Ile Thr
Leu Asn Leu Thr Ile Met Asn Val
Ser Leu Gln Asp Ser Gly Thr Tyr
Ala Cys Arg Ala Arg Asn Val Tyr
Thr Gly Glu Glu Ile Leu Gln Lys
Lys Glu Ile Thr Ile Arg Gly Glu
His Cys Asn Lys Lys Ala Val Phe
Ser Arg Ile Set Lys Phe Lys Set
Thr Arg Asn Asp Cys Thr Thr Gln
Set Asn Val Lys His.
5 . The soluble VEGF inhibitor of claim 2 corresponding to sVEGF-RII comprising the amino acid sequence:
MQSKVLLAVALWLCVETRAASVGLPSVSLDLP
(SEQ. ID. NO.:13)
RLSIQKDILTIKANTTLQITCRGQRDLDWLWP
NNQSGSEQRVEVTECSDGLFCKTLTIPKVIGN
DTGAYKCFYRETDLASVIYVYVQDYRSPFIAS
VSDQHGVVYITENKNKTVVIPCLGSISNLNVS
LCARYPEKRFVPDGNRISWDSKKGFTIPSYMI
SYAGMVFCEAKINDESYQSIMYIVVVVGYRIY
DVVLSPSHGIELSVGEKLVLNCTARTELNVGI
DFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKF
LSTLTIDGVTRSDQGLYTCAASSGLMTKKNST
FVRVHEKPFVAFGSGMESLVEATVGERVRIPA
KYLGYPPPEIKWYKNGIPLESNHTIKAGHVLT
IMEVSERDTGNYTVILTNPISKEKQSHVVSLV
VYVPPQIGEKSLISPVDSYQYGTTQTLTCTVY
AIPPPHHIHWYWQLEEECANEPSQAVSVTNPY
PCEEWRSVEDFQGGNKIAVNKNQFALIEGKNK
TVSTLVIQAANVSALYKCEAVNKVGRGERVIS
FHVTRGPEITLQPDMQPTEQESVSLWCTADRS
TFENLTWYKLGPQPLPIHVGELPTPVCKNLDT
LWKLNATMFSNSTNDILIMELKNASLQDQGDY
VCLAQDRKTKKRHCVVRQLTVLER.
6 . The soluble VEGF inhibitor of claim 2 corresponding to sVEGF-RTMI comprising the amino acid sequence:
MVSYWDTGVLLCALLSCLLLTGSSSGSKLKDP
(SEQ. ID. NO.:14)
ELSLKGTQHIMQAGQTLHLQCRGEAAHKWSLP
EMVSKESERLSITKSACGRNGKQFCSTLTLNT
AQANHTGFYSCKYLAVPTSKKKETESAIYIFI
SDTGRPFVEMYSEIPEIIHMTEGRELVIPCRV
TSPNITVTLKKFPLDTLIPDGKRIIWDSRKGF
IISNATYKEIGLLTCEATVNGHLYKTNYLTHR
QTNTIIDVQISTPRPVKLLRGHTLVLNCTATT
PLNTRVQMTWSYPDEKNKRASVRRRIDQSNSH
ANIFYSVLTIDKMQNKDKGLYTCRVRSGPSFK
SVNTSVHIYDKAFITVKHRKQQVLETVAGKRS
YRLSMKVKAFPSPEVVWLKDGLPATEKSARYL
TRGYSLIIKDVTEEDAGNYTILLSIKQSNVFK
NLTATLIVNVKPQIYEKAVSSFPDPALYPLGS
RQILTCTAYGIPQPTIKWFWHPCNHNHSEARC
DFCSNNEESFILDADSNMGNRIESITQRMAII
EGKNKMASTLVVADSRISGIYICIASNKVGTV
GRNISFYITDVPNGFHVNLEKMPTEGEDLKLS
CTVNKFLYRDVTWILLRTVNNRTMHYSISKQK
MAITKEHSITLNLTIMNVSLQDSGTYACRARN
VYTGEEILQKKEITIRDQEAPYLLRNLSDHTV
AISSSTTLDCHANGVPEPQITWFKNNHKIQQE
PGIILGPGSSTLFIERVTEEDEGVYHCKATNQ
KGSVESSAYLTVQGTSDKSNLELITLTCTCVA
ATLFWLLLTLLI.
7 . The soluble VEGF inhibitor of claim 2 corresponding to sVEGF-RTMII comprising the amino acid sequence:
MQSKVLLAVALWLCVETRAASVGLPSVSLDLP
(SEQ. ID. NO.:15)
RLSIQKDILTIKANTTLQITCRGQRDLDWLWP
NNQSGSEQRVEVTECSDGLFCKTLTIPKVIGN
DTGAYKCFYRETDLASVIYVYVQDYRSPFIAS
VSDQHGVVYITENKNKTVVIPCLGSISNLNVS
LCARYPEKRFVPDGNRISWDSKKGFTIPSYMI
SYAGMVFCEAKINDESYQSIMYIVVVVGYRIY
DVVLSPSHGIELSVGEKLVLNCTARTELNVGI
DFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKF
LSTLTIDGVTRSDQGLYTCAASSGLMTKKNST
FVRVHEKPFVAFGSGMESLVEATVGERVRIPA
KYLGYPPPEIKWYKNGIPLESNHTIKAGHVLT
IMEVSERDTGNYTVILTNPISKEKQSHVVSLV
VYVPPQIGEKSLISPVDSYQYGTTQTLTCTVY
AIPPPHHIHWYWQLEEECANEPSQAVSVTNPY
PCEEWRSVEDFQGGNKIAVNKNQFALIEGKNK
TVSTLVIQAANVSALYKCEAVNKVGRGERVIS
FHVTRGPEITLQPDMQPTEQESVSLWCTADRS
TFENLTWYKLGPQPLPIHVGELPTPVCKNLDT
LWKLNATMFSNSTNDILIMELKNASLQDQGDY
VCLAQDRKTKKRHCVVRQLTVLERVAPTITGN
LENQTTSIGESIEVSCTASGNPPPQIMWFKDN
ETLVEDSGIVLKDGNRNLTIRRVRKEDEGLYC
QACSVLGCAKVEAFFIIEGAQEKTNLEIIILV
GTTVIAMFFWLLLVIILGTV.
8 . An expression vector comprising a promoter, and a DNA sequence encoding a soluble VEGF inhibitor for expression in recombinant host cells wherein the soluble VEGF inhibitor is selected from the group consisting of sVEGF-RI, sVEGF-RII, sVEGF-RTMI and sVEGF-RTMII.
9 . The expression vector of claim 8 wherein the DNA encoding the sVEGF-RI comprises the nucleotide sequence:
GCGGACACTCCTCTCGGCTCCTCCCCGGCAGCGG
(SEQ. ID. NO.:5)
CGGCGGCTCGGAGCGGGCTCCGGGGCTCGGGTGC
AGCGGCCAGCGGGCCTGGCGGCGAGGATTACCCG
GGGAAGTGGTTGTCTCCTGGCTGGAGCCGCGAGA
CGGGCGCTCAGGGCGCGGGGCCGGCGGCGGCGAA
CGAGAGGACGGACTCTGGCGGCCGGGTCGTTGGC
CGGGGGAGCGCGGGCACCGGGCGAGCAGGCCGCG
TCGCGCTCACC ATG GTC AGC TAC TGG
GAC ACC GGG GTC CTG CTG TGC GCG
CTG CTC AGC TGT CTG CTT CTC ACA
GGA TCT AGT TCA GGT TCA AAA TTA
AAA GAT CCT GAA CTG AGT TTA AAA
GGC ACC CAG CAC ATC ATG CAA GCA
GGC CAG ACA CTG CAT CTC CAA TGC
AGG GGG GAA GCA GCC CAT AAA TGG
TCT TTG CCT GAA ATG GTG AGT AAG
GAA AGC GAA AGG CTG AGC ATA ACT
AAA TCT GCC TGT GGA AGA AAT GGC
AAA CAA TTC TGC AGT ACT TTA ACC
TTG AAC ACA GCT CAA GCA AAC CAC
ACT GGC TTC TAC AGC TGC AAA TAT
CTA GCT GTA CCT ACT TCA AAG AAG
AAG GAA ACA GAA TCT GCA ATC TAT
ATA TTT ATT AGT GAT ACA GGT AGA
CCT TTC GTA GAG ATG TAC AGT GAA
ATC CCC GAA ATT ATA CAC ATG ACT
GAA GGA AGG GAG CTC GTC ATT CCC
TGC CGG GTT ACG TCA CCT AAC ATC
ACT GTT ACT TTA AAA AAG TTT CCA
CTT GAC ACT TTG ATC CCT GAT GGA
AAA CGC ATA ATC TGG GAC AGT AGA
AAG GGC TTC ATC ATA TCA AAT GCA
ACG TAC AAA GAA ATA GGG CTT CTG
ACC TGT GAA GCA ACA GTC AAT GGG
CAT TTG TAT AAG ACA AAC TAT CTC
ACA CAT CGA CAA ACC AAT ACA ATC
ATA GAT GTC CAA ATA AGC ACA CCA
CGC CCA GTC AAA TTA CTT AGA GGC
CAT ACT CTT GTC CTC AAT TGT ACT
GCT ACC ACT CCC TTG AAC ACG AGA
GTT CAA ATG ACC TGG AGT TAC CCT
GAT GAA AAA AAT AAG AGA GCT TCC
GTA AGG CGA CGA ATT GAC CAA AGC
AAT TCC CAT GCC AAC ATA TTC TAC
AGT GTT CTT ACT ATT GAC AAA ATG
CAG AAC AAA GAC AAA GGA CTT TAT
ACT TGT CGT GTA AGG AGT GGA CCA
TCA TTC AAA TCT GTT AAC ACC TCA
GTG CAT ATA TAT GAT AAA GCA TTC
ATC ACT GTG AAA CAT CGA AAA CAG
CAG GTG CTT GAA ACC GTA GCT GGC
AAG CGG TCT TAC CGG CTC TCT ATG
AAA GTG AAG GCA TTT CCC TCG CCG
GAA GTT GTA TGG TTA AAA GAT GGG
TTA CCT GCG ACT GAG AAA TCT GCT
CGC TAT TTG ACT CGT GGC TAC TCG
TTA ATT ATC AAG GAC GTA ACT GAA
GAG GAT GCA GGG AAT TAT ACA ATC
TTG CTG AGC ATA AAA CAG TCA AAT
GTG TTT AAA AAC CTC ACT GCC ACT
CTA ATT GTC AAT GTG AAA CCC CAG
ATT TAC GAA AAG GCC GTG TCA TCG
TTT CCA GAC CCG GCT CTC TAC CCA
CTG GGC AGC AGA CAA ATC CTG ACT
TGT ACC GCA TAT GGT ATC CCT CAA
CCT ACA ATC AAG TGG TTC TGG CAC
CCC TGT AAC CAT AAT CAT TCC GAA
GCA AGG TGT GAC TTT TGT TCC AAT
AAT GAA GAG TCC TTT ATC CTG GAT
GCT GAC AGC AAC ATG GGA AAC AGA
ATT GAG AGC ATC ACT CAG CGC ATG
GCA ATA ATA GAA GGA AAG AAT AAG
ATG GCT AGC ACC TTG GTT GTG GCT
GAC TCT AGA ATT TCT GGA ATC TAC
ATT TGC ATA GCT TCC AAT AAA GTT
GGG ACT GTG GGA AGA AAC ATA AGC
TTT TAT ATC ACA GAT GTG CCA AAT
GGG TTT CAT GTT AAC TTG GAA AAA
ATG CCG ACG GAA GGA GAG GAC CTG
AAA CTG TCT TGC ACA GTT AAC AAG
TTC TTA TAC AGA GAC GTT ACT TGG
ATT TTA CTG CGG ACA GTT AAT AAC
AGA ACA ATG CAC TAC AGT ATT AGC
AAG CAA AAA ATG GCC ATC ACT AAG
GAG CAC TCC ATC ACT CTT AAT CTT
ACC ATC ATG AAT GTT TCC CTG CAA
GAT TCA GGC ACC TAT GCC TGC AGA
GCC AGG AAT GTA TAC ACA GGG GAA
GAA ATC CTC CAG AAG AAA GAA ATT
ACA ATC AGA GGT GAG CAC TGC AAC
AAA AAG GCT GTT TTC TCT CGG ATC
TCC AAA TTT AAA AGC ACA AGG AAT
GAT TGT ACC ACA CAA AGT AAT GTA
AAA CAT TAA AGGACTCATTAAAAAGTAACAG
TTGTCTCATATCATCTTGATTTATTGTCACTGTT
GCTAACTTTCAGGCTCGGAGGAGATGCTCCTCCC
AAAATGAGTTCGGAGATGATAGCAGTAATAATGA
GACCCCCGGGCTCCAGCTCTGGGCCCCCCATTCA
GGCCGAGGGGGCTGCTCCGGGGGGCCGACTTGGT
GCACGTTTGGATTTGGAGGATCCCTGCACTGCCT
TCTCTGTGTTTGTTGCTCTTGCTGTTTTCTCCTG
CCTGATAAACAACAACTTGGGATGATCCTTTCCA
TTTTGATGCCAACCTCTTTTTATTTTTAAGCGGC
GCCCTATAGT.
10 . The expression vector of claim 8 wherein the DNA encoding the sVEGF-RII comprises the nucleotide sequence:
GGTGTGGTCGCTGCGTTTCCTCTGCCTGCGCC
(SEQ. ID. NO.:16)
GGGCATCACTTGCGCGCCGCAGAAAGTCCGTC
TGGCAGCCTGGATATCCTCTCCTACCGGCACC
CGCAGACGCCCCTGCAGCCGCGGTCGGCGCCC
GGGCTCCCTAGCCCTGTGCGCTCAACTGTCCT
GCGCTGCGGGGTGCCGCGAGTTCCACCTCCGC
GCCTCCTTCTCTAGACAGGCGCTGGGAGAAAG
AACCGGCTCCCGAGTTCCGGCATTTCGCCCGG
CTCGAGGTGCAGGATGCAGAGCAAGGTGCTGC
TGGCCGTCGCCCTGTGGCTCTGCGTGGAGACC
CGGGCCGCCTCTGTGGGTTTGCCTAGTGTTTC
TCTTGATCTGCCCAGGCTCAGCATACAAAAAG
ACATACTTACAATTAAGGCTAATACAACTCTT
CAAATTACTTGCAGGGGACAGAGGGACTTGGA
CTGGCTTTGGCCCAATAATCAGAGTGGCAGTG
AGCAAAGGGTGGAGGTGACTGAGTGCAGCGAT
GGCCTCTTCTGTAAGACACTCACAATTCCAAA
AGTGATCGGAAATGACACTGGAGCCTACAAGT
GCTTCTACCGGGAAACTGACTTGGCCTCGGTC
ATTTATGTCTATGTTCAAGATTACAGATCTCC
ATTTATTGCTTCTGTTAGTGACCAACATGGAG
TCGTGTACATTACTGAGAACAAAAACAAAACT
GTGGTGATTCCATGTCTCGGGTCCATTTCAAA
TCTCAACGTGTCACTTTGTGCAAGATACCCAG
AAAAGAGATTTGTTCCTGATGGTAACAGAATT
TCCTGGGACAGCAAGAAGGGCTTTACTATTCC
CAGCTACATGATCAGCTATGCTGGCATGGTCT
TCTGTGAAGCAAAAATTAATGATGAAAGTTAC
CAGTCTATTATGTACATAGTTGTCGTTGTAGG
GTATAGGATTTATGATGTGGTTCTGAGTCCGT
CTCATGGAATTGAACTATCTGTTGGAGAAAAG
CTTGTCTTAAATTGTACAGCAAGAACTGAACT
AAATGTGGGGATTGACTTCAACTGGGAATACC
CTTCTTCGAAGCATCAGCATAAGAAACTTGTA
AACCGAGACCTAAAAACCCAGTCTGGGAGTGA
GATGAAGAAATTTTTGAGCACCTTAACTATAG
ATGGTGTAACCCGGAGTGACCAAGGATTGTAC
ACCTGTGCAGCATCCAGTGGGCTGATGACCAA
GAAGAACAGCACATTTGTCAGGGTCCATGAAA
AACCTTTGTTGCTTTTGGAAGTGGCATGGAAT
CTCTGGTGGAAGCCACGGTGGGGGAGCGTGTC
AGAATCCCTGCGAAGTACCTTGGTTACCCACC
CCCAGAAATAAAATGGTATAAAAATGGAATAC
CCCTTGAGTCCAATCACACAATTAAAGCGGGG
CATGTACTGACGATTATGGAAGTGAGTGAAAG
AGACACAGGAAATTACACTGTCATCCTTACCA
ATCCCATTTCAAAGGAGAAGCAGAGCCATGTG
GTCTCTCTGGTTGTGTATGTCCCACCCCAGAT
TGGTGAGAAATCTCTAATCTCTCCTGTGGATT
CCTACCAGTACGGCACCACTCAAACGCTGACA
TGTACGGTCTATGCCATTCCTCCCCCGCATCA
CATCCACTGGTATTGGCAGTTGGAGGAAGAGT
GCGCCAACGAGCCCAGCCAAGCTGTCTCAGTG
ACAAACCCATACCCTTGTGAAGAATGGAGAAG
TGTGGAGGACTTCCAGGGAGGAAATAAAATTG
CCGTTAATAAAAATCAATTTGCTCTAATTGAA
GGAAAAAACAAAACTGTAAGTACCCTTGTTAT
CCAAGCGGCAAATGTGTCAGCTTTGTACAAAT
GTGAAGCGGTCAACAAAGTCGGGAGAGGAGAG
AGGGTGATCTCCTTCCACGTGACCAGGGGTCC
TGAAATTACTTTGCAACCTGACATGCAGCCCA
CTGAGCAGGAGAGCGTGTCTTTGTGGTGCACT
GCAGACAGATCTACGTTTGAGAACCTCACATG
GTACAAGCTTGGCCCACAGCCTCTGCCAATCC
ATGTGGGAGAGTTGCCCACACCTGTTTGCAAG
AACTTGGATACTCTTTGGAAATTGAATGCCAC
CATGTTCTCTAATAGCACAAATGACATTTTGA
TCATGGAGCTTAAGAATGCATCCTTGCAGGAC
CAAGGAGACTATGTCTGCCTTGCTCAAGACAG
GAAGACCAAGAAAAGACATTGCGTGGTCAGGC
AGCTCACAGTCCTAGAGCGTTAA.
11 . The expression vector of claim 8 wherein the DNA encoding the sVEGF-RTMI comprises the nucleotide sequence:
GCGCTCACCATGGTCAGCTACTGGGACACCGG
(SEQ. ID. NO.:17)
GGTCCTGCTGTGCGCGCTGCTCAGCTGTCTGC
TTCTCACAGGATCTAGTTCAGGTTCAAAATTA
AAAGATCCTGAACTGAGTTTAAAAGGCACCCA
GCACATCATGCAAGCAGGCCAGACACTGCATC
TCCAATGCAGGGGGGAAGCAGCCCATAAATGG
TCTTTGCCTGAAATGGTGAGTAAGGAAAGCGA
AAGGCTGAGCATAACTAAATCTGCCTGTGGAA
GAAATGGCAAACAATTCTGCAGTACTTTAACC
TTGAACACAGCTCAAGCAAACCACACTGGCTT
CTACAGCTGCAAATATCTAGCTGTACCTACTT
CAAAGAAGAAGGAAACAGAATCTGCAATCTAT
ATATTTATTAGTGATACAGGTAGACCTTTCGT
AGAGATGTACAGTGAAATCCCCGAAATTATAC
ACATGACTGAAGGAAGGGAGCTCGTCATTCCC
TGCCGGGTTACGTCACCTAACATCACTGTTAC
TTTAAAAAAGTTTCCACTTGACACTTTGATCC
CTGATGGAAAACGCATAATCTGGGACAGTAGA
AAGGGCTTCATCATATCAAATGCAACGTACAA
AGAAATAGGGCTTCTGACCTGTGAAGCAACAG
TCAATGGGCATTTGTATAAGACAAACTATCTC
ACACATCGACAAACCAATACAATCATAGATGT
CCAAATAAGCACACCACGCCCAGTCAAATTAC
TTAGAGGCCATACTCTTGTCCTCAATTGTACT
GCTACCACTCCCTTGAACACGAGAGTTCAAAT
GACCTGGAGTTACCCTGATGAAAAAAATAAGA
GAGCTTCCGTAAGGCGACGAATTGACCAAAGC
AATTCCCATGCCAACATATTCTACAGTGTTCT
TACTATTGACAAAATGCAGAACAAAGACAAAG
GACTTTATACTTGTCGTGTAAGGAGTGGACCA
TCATTCAAATCTGTTAACACCTCAGTGCATAT
ATATGATAAAGCATTCATCACTGTGAAACATC
GAAAACAGCAGGTGCTTGAAACCGTAGCTGGC
AAGCGGTCTTACCGGCTCTCTATGAAAGTGAA
GGCATTTCCCTCGCCGGAAGTTGTATGGTTAA
AAGATGGGTTACCTGCGACTGAGAAATCTGCT
CGCTATTTGACTCGTGGCTACTCGTTAATTAT
CAAGGACGTAACTGAAGAGGATGCAGGGAATT
ATACAATCTTGCTGAGCATAAAACAGTCAAAT
GTGTTTAAAAACCTCACTGCCACTCTAATTGT
CAATGTGAAACCCCAGATTTACGAAAAGGCCG
TGTCATCGTTTCCAGACCCGGCTCTCTACCCA
CTGGGCAGCAGACAAATCCTGACTTGTACCGC
ATATGGTATCCCTCAACCTACAATCAAGTGGT
TCTGGCACCCCTGTAACCATAATCATTCCGAA
GCAAGGTGTGACTTTTGTTCCAATAATGAAGA
GTCCTTTATCCTGGATGCTGACAGCAACATGG
GAAACAGAATTGAGAGCATCACTCAGCGCATG
GCAATAATAGAAGGAAAGAATAAGATGGCTAG
CACCTTGGTTGTGGCTGACTCTAGAATTTCTG
GAATCTACATTTGCATAGCTTCCAATAAAGTT
GGGACTGTGGGAAGAAACATAAGCTTTTATAT
CACAGATGTGCCAAATGGGTTTCATGTTAACT
TGGAAAAAATGCCGACGGAAGGAGAGGACCTG
AAACTGTCTTGCACAGTTAACAAGTTCTTATA
CAGAGACGTTACTTGGATTTTACTGCGGACAG
TTAATAACAGAACAATGCACTACAGTATTAGC
AAGCAAAAAATGGCCATCACTAAGGAGCACTC
CATCACTCTTAATCTTACCATCATGAATGTTT
CCCTGCAAGATTCAGGCACCTATGCCTGCAGA
GCCAGGAATGTATACACAGGGGAAGAAATCCT
CCAGAAGAAAGAAATTACAATCAGAGATCAGG
AAGCACCATACCTCCTGCGAAACCTCAGTGAT
CACACAGTGGCCATCAGCAGTTCCACCACTTT
AGACTGTCATGCTAATGGTGTCCCCGAGCCTC
AGATCACTTGGTTTAAAAACAACCACAAAATA
CAACAAGAGCCTGGAATTATTTTAGGACCAGG
AAGCAGCACGCTGTTTATTGAAAGAGTCACAG
AAGAGGATGAAGGTGTCTATCACTGCAAAGCC
ACCAACCAGAAGGGCTCTGTGGAAAGTTCAGC
ATACCTCACTGTTCAAGGAACCTCGGACAAGT
CTAATCTGGAGCTGATCACTCTAACATGCACC
TGTGTGGCTGCGACTCTCTTCTGGCTCCTATT
AACCCTCCTTATCTAA.
12 . The expression vector of claim 8 wherein the DNA encoding the sVEGF-RTMII comprises the nucleotide sequence:
(SEQ. ID. NO.: 18)
CTCGAGGTGCAGGATGCAGAGCAAGGTGCTGCTGGCCGTCGCCCTGTGGC
TCTGCGTGGAGACCCGGGCCGCCTCTGTGGGTTTGCCTAGTGTTTCTCTT
GATCTGCCCAGGCTCAGCATACAAAAAGACATACTTACAATTAAGGCTAA
TACAACTCTTCAAATTACTTGCAGGGGACAGAGGGACTTGGACTGGCTTT
GGCCCAATAATCAGAGTGGCAGTGAGCAAAGGGTGGAGGTGACTGAGTGC
AGCGATGGCCTCTTCTGTAAGACACTCACAATTCCAAAAGTGATCGGAAA
TGACACTGGAGCCTACAAGTGCTTCTACCGGGAAACTGACTTGGCCTCGG
TCATTTATGTCTATGTTCAAGATTACAGATCTCCATTTATTGCTTCTGTT
AGTGACCAACATGGAGTCGTGTACATTACTGAGAACAAAAACAAAACTGT
GGTGATTCCATGTCTCGGGTCCATTTCAAATCTCAACGTGTCACTTTGTG
CAAGATACCCAGAAAAGAGATTTGTTCCTGATGGTAACAGAATTTCCTGG
GACAGCAAGAAGGGCTTTACTATTCCCAGCTACATGATCAGCTATGCTGG
CATGGTCTTCTGTGAAGCAAAAATTAATGATGAAAGTTACCAGTCTATTA
TGTACATAGTTGTCGTTGTAGGGTATAGGATTTATGATGTGGTTCTGAGT
CCGTCTCATGGAATTGAACTATCTGTTGGAGAAAAGCTTGTCTTAAATTG
TACAGCAAGAACTGAACTAAATGTGGGGATTGACTTCAACTGGGAATACC
CTTCTTCGAAGCATCAGCATAAGAAACTTGTAAACCGAGACCTAAAAACC
CAGTCTGGGAGTGAGATGAAGAAATTTTTGAGCACCTTAACTATAGATGG
TGTAACCCGGAGTGACCAAGGATTGTACACCTGTGCAGCATCCAGTGGGC
TGATGACCAAGAAGAACAGCACATTTGTCAGGGTCCCATGAAAAACCTTT
GTTGCTTTTGGAAGTGGCATGGAATCTCTGGTGGAAGCCACGGTGGGGGA
GCGTGTCAGAATCCCTGCGAAGTACCTTGGTTACCCACCCCCAGAAATAA
AATGGTATAAAAATGGAATACCCCTTGAGTCCAATCACACAATTAAAGCG
GGGCATGTACTGACGAATATGGAAGTGAGTGAAAGAGACACAGGAAATTA
CACTGTCATCCTTACCAATCCCATTTCAAAGGAGAAGCAGAGCCATGTGG
TCTCTCTGGTTGTGTATGTCCCACCCCAGATTGGTGAGAAATCTCTAATC
TCTCCTGTGGATTCCTACCAGTACGGCACCACTCAAACGCTGACATGTAC
GGTCTATGCCATTCCTCCCCCGCATCACATCCACTGGTATTGGCAGTTGG
AGGAAGAGTGCGCCAACGAGCCCAGCCAAGCTGTCTCAGTGACAAACCCA
TACCCTTGTGAAGAATGGAGAAGTGTGGAGGACTTCCAGGGAGGAAATAA
AATTGCCGTTAATAAAAATCAATTTGCTCTAATTGAAGGAAAAAACAAAA
CTGTAAGTACCCTTGTTATCCAAGCGGCAAATGTGTCAGCTTTGTACAAA
TGTGAAGCGGTCAACAAAGTCGGGAGAGGAGAGAGGGTCTGACATGCAGC
CCACTGAGCAGGAGAGCGTGTCTTTGTGGTGCACTGCAGACAGATCTACG
TTTGAGAACCTCACATGGTACAAGCTTGGCCCACAGCCTCTGCCAATCCA
TGTGGGAGAGTTGCCCACACCTGTTTGCAAGAACTTGGATACTCTTTGGA
AATTGAATGCCACCATGTTCTCTAATAGCACAAATGACATTTTGATCATG
GAGCTTAAGAATGCATCCTTGCAGGACCAAGGAGACTATGTCTGCCTTGC
TCAAGACAGGAAGACCAAGAAAAGACATTGCGTGGTCAGGCAGCTCACAG
TCCTAGAGCGTGTGGCACCCACGATCACAGGAAACCTGGAGAATCAGACG
ACAAGTATTGGGGAAAGCATCGAAGTCTCATGCACGGCATCTGGGAATCC
CCCTCCACAGATCATGTGGTTTAAAGATAATGAGACCCTTGTAGAAGACT
CAGGCATTGTATTGAAGGATGGGAACCGGAACCTCACTATCCGCAGAGTG
AGGAAGGAGGACGAAGGCCTCTACACCTGCCAGGCATGCAGTGTTCTTGG
CTGTGCAAAAGTGGAGGCATTTTTCATAATAGAAGGTGCCCAGGAAAAGA
CGAACTTGGAAATCATTATTCTAGTAGGCACGACGGTGATTGCCATGTTC
TTCTGGCTACTTCTTGTCATCATCCTAGGGACCGTTTAA.
13 . A recombinant host cell containing the expression vector of claim 8 .
14 . A method for inhibiting VEGF receptor function comprising the administration of the VEGF inhibitor of claim 1 in an amount sufficient to inhibit VEGF receptor function.
15 . The method of claim 14 wherein the VEGF inhibitor is selected from the group consisting of sVEGF-RI, sVEGF-RII, sVEGF-RTMI, and sVEGF-RTMII.
16 . A pharmaceutical composition comprising the inhibitor of claim 1 and a pharmaceutically acceptable carrier.
17 . The pharmaceutical composition of claim 16 wherein the inhibitor is selected from the group consisting of sVEGF-RI, sVEGF-RII, sVEGF-RTMI, and sVEGF-RTMII.
18 . A method for inhibiting angiogenesis comprising the administration of the VEGF inhibitor of claim 1 in an amount sufficient to inhibit angiogensis.Join the waitlist — get patent alerts
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