CA2595037A1 - Modified tie-2 receptor ligands - Google Patents

Modified tie-2 receptor ligands Download PDF

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Publication number
CA2595037A1
CA2595037A1 CA002595037A CA2595037A CA2595037A1 CA 2595037 A1 CA2595037 A1 CA 2595037A1 CA 002595037 A CA002595037 A CA 002595037A CA 2595037 A CA2595037 A CA 2595037A CA 2595037 A1 CA2595037 A1 CA 2595037A1
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Canada
Prior art keywords
leu
glu
gln
asn
ser
Prior art date
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Abandoned
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CA002595037A
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French (fr)
Inventor
Samuel Davis
George D. Yancopoulos
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Regeneron Pharmaceuticals Inc
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Individual
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Filing date
Publication date
Priority claimed from US08/740,223 external-priority patent/US6265564B1/en
Application filed by Individual filed Critical Individual
Publication of CA2595037A1 publication Critical patent/CA2595037A1/en
Abandoned legal-status Critical Current

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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts

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  • Peptides Or Proteins (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Enzymes And Modification Thereof (AREA)

Abstract

The present invention provides for a modified TIE-2 ligand which has been altered by addition, deletion or substitution of one or more amino acids, or by way of tagging, with for example, the Fc portion of human IgG-1, but which retains its ability ,to bind the TIE-2 receptor. The invention further provides for a modified TIE-2 ligand which is a chimeric TIE-2 ligand comprising at least a portion of a first TIE-2 ligand and a portion of a second TIE-2 ligand which is different from the first. In a specific embodiment, the invention further provides for a chimeric TIE ligand comprising at least a portion of TIE-2 ligand-1 and a portion of TIE-2 ligand-2. In addition the present invention provides for isolated nucleic acid molecule encoding the modified TIE-2 ligands described. The invention also provides for therapeutic compositions as well as a method of blocking blood vessel growth, a method of promoting neovascularization, a method of promoting the growth or differentiation of a cell expressing the TIE receptor, a method of blocking the growth or differentiation of a cell expressing the TIE receptor and a method of attenuating or preventing tumor growth in a human

Description

D E~!LA.~~~~~ OU BREVETS VOLU1~ITNEUX
LA PRESENTE Pz~.RTIE DE CETTE DENL.,0DE OU CE .DpEVT-TS
CONIPREND PLUS D'tUyN TOME.

CECI EST LE TOINIE q4,- DE

NOTE: Pour les tomes additionels, veillez contacter le Bureau Canadien des Brevets.
J-U~~~~ APPLICATIONS ~ PATENTS

THIS SECTION OF THE APPLICATION / PATENT CON TAil'iiS NIORE
THAN ONE VOLUNIE.

,-2 THIS IS VOLUiVIE <- OF ' NOTE: For additional volumes olease contact the Canadian Patent Office.

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SEQUENCE LISTING
(1) GENERAL INFORMATION

(i) APPLICANT: Regeneron Pharmaceuticals, Inc.

(ii) TITLE OF THE INVENTION: "Modified Tie-2-Receptor Ligands"
(iii) NUMBER OF SEQUENCES: 28 (iv) CORRESPONDENCE ADDRESS:
(A) ADDRESSEE: Osler, Hoskin & Harcourt (B) STREET: 50 O'Connor Street, Suite 1500 (C) CITY: Ottawa (D) STATE: Ontario (E) COUNTRY: Canada (F) ZIP: K1P 6L2 (v) COMPUTER READABLE FORM:
(A) MEDIUM TYPE: Diskette (B) COMPUTER: IBM Compatible (C) OPERATING SYSTEM: DOS
(D) SOFTWARE: FastSEQ Version 2.0 (vi) CURRENT APPLICATION DATA:
(A) APPLICATION NUMBER: 2,262,409 (B) FILING DATE: 25-OCT-1996 (C) CLASSIFICATION:

(vii) PRIOR APPLICATION DATA:
(A) APPLICATION NUMBER: USSN 60/022/999 (B) FILING DATE: August 1, 1997 (viii) ATTORNEY/AGENT INFORMATION:
(A) NAME: David W. Aitken (B) REFERENCE/DOCKET NUMBER: 13464 (ix) TELECOMMUNICATION INFORMATION:
(A) TELEPHONE: 613-787-7234 (B) TELEFAX: 613-235-2867
(2) INFORMATION FOR SEQ ID NO:1:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 2149 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY:' linear (ii) MOLECULE TYPE: DNA
(ix) FEATURE:

(A) NAME/KEY: Coding Sequence (B) LOCATION: 310...1803 (D) OTHER INFORMATION:

(A) NAME/KEY: Human TIE-2 ligand 1 (B) LOCATION: 1...2149 (D) OTHER INFORMATION: from clone gt10 encoding htie-2 ligand 1 (xi) SEQUE-NCE DESCRIPTION: SEQ ID N0:1:
CAGCTGACTC AGGCAGGCTC CATGCTGAAC GGTCACACAG

GCTACTATGC AATAAATATC TCAAGTTTTA ACGAAGAAAA

AAAATTTTAA AATTTTAGAA CAAAGCTAAC AAATGGCTAG

AACGCTTTCT TTGAGGGGGA AAGAGTCAAA CAAACAAGCA

CTAGTTTTAG AGGTCAGAAG AAAGGAGCAA GTTTTGCGAG
AGGCACGGAA GGAGTGTGCT 300 '1 GGCAGTACA ATG ACA GTT TTC CTT TCC TTT GCT TTC CTC GCT GCC

Met Thr Val Phe Leu Ser Phe Ala Phe Leu Ala Ala Ile Leu ACT CAC ATA GGG TGC AGC AAT CAG CGC CGA AGT CCA GAA AAC

Thr His Ile Gly Cys Ser Asn Gln Arg Arg Ser Pro Glu Asn Ser Gly AGA AGA TAT AAC CGG ATT CAA CAT GGG CAA TGT GCC TAC ACT TTC

Arg Arg Tyr Asn Arg Ile Gln His Gly Gln Cys Ala Tyr Thr Phe Ile CTT CCA GAA CAC GAT GGC AAC TGT CGT GAG AGT ACG ACAGAC

Leu Pro Glu His Asp Gly Asn Cys Arg Glu Ser Thr Thr Asp Gln Tyr AAC ACA AAC GCT CTG CAG AGA GAT GCT CCA CAC GTG GAA CCG

Asn Thr Asn Ala Leu Gln Arg Asp Ala Pro His Val Glu Pro Asp Phe TCT TCC CAG AAA CTT CAA CAT CTG GAA CAT GTG ATG GAA AAT TAT

Ser Ser Gln Lys Leu Gln His Leu Glu His Val Met Glu Asn Tyr Thr CAG TGG CTG CAA AAA CTT GAG AAT TAC ATT GTG GAA AAC ATG

Gln Trp Leu Gln Lys Leu Glu Asn Tyr Ile Val Glu Asn Met Lys Ser GAG ATG GCC CAG ATA CAG CAG AAT GCA GTT CAG AAC CAC ACG

Glu Met Ala Gln Ile Gln Gln Asn Ala Val Gln Asn His Thr Ala Thr ATG CTG GAG ATA GGA ACC AGC CTC CTC TCT CAG ACT GCA GAG

Met Leu Glu Ile Gly Thr Ser Leu Leu Ser Gln Thr Ala Giu Gln Thr AGA AAG CTG ACA GAT GTT GAG ACC CAG GTA CTA AAT CAA ACT TCT

Arq Lys Leu Thr Asp Val Glu Thr Gin Val Leu Asn Gln Thr Ser Arg CTT GAG ATA CAG CTG CTG GAG AAT TCA TTA TCC ACC TAC AAG CTA

Leu Glu Ile Gln Leu Leu Glu Asn Ser Leu Ser Thr Tyr Lys Leu Glu 160 1,65 170 AAG CAA CTT CTT CAA CAG ACA AAT GAA ATC TTG AAG ATC CAT GAA

Lys Gln Leu Leu Gln Gln Thr Asn Glu Ile Leu Lys Ile His Glu Lys AAC AGT TTA TTA GAA CAT AAA ATC TTA GAA ATG GAA GGA AAA

Asn Ser Leu Leu Glu His Lys Ile Leu Glu Met Glu Gly Lys His Lys GAA GAG TTG GAC ACC TTA AAG GAA GAG AAA GAG AAC CTT CAA

Glu Glu Leu Asp Thr Leu Lys Glu Glu Lys Giu Asn Leu Gln Gly Leu GTT ACT CGT CAA ACA TAT ATA ATC CAG GAG CTG GAA AAG CAA TTA

Val Thr Arg Gln Thr Tyr Ile Ile Gin Glu Leu Giu Lys Gln Leu Asn AGA GCT ACC ACC AAC AAC AGT GTC CTT CAG AAG,CAG CAA CTG

Arg Ala Thr Thr Asn Asn Ser Val Leu Gin Lys Gln Gln Leu Glu Leu ATG GAC ACA GTC CAC AAC CTT GTC AAT CTT TGC ACT AAA GAA GGT

Met Asp Thr Val His Asn Leu Val Asn Leu Cys Thr Lys Glu Gly Val TTA CTA AAG GGA GGA AAA AGA GAG GAA GAG AAA CCA TTT AGA

Leu Leu Lys Gly Gly Lys Arg Glu Glu Glu Lys Pro Phe Arg Asp Cys GCA GAT GTA TAT CAA GCT GGT TTT AAT AAA AGT GGA ATC TAC ACT

Ala Asp Val Tyr Gln Ala Gly Phe Asn Lys Ser Gly Ile Tyr Thr Ile TAT ATT AAT AAT ATG CCA GAA CCC AAA AAG GTG TTT TGC AAT ATG

Tyr Ile Asn Asn Met Pro Glu Pro Lys Lys Val Phe Cys Asn Met Asp GTC AAT GGG GGA GGT TGG ACT GTA ATA CAA CAT CGT GAA GAT

Val Asn Gly Gly Gly Trp Thr Val Ile Gln His Arg Glu Asp Gly Ser CTA GAT TTC CAA AGA GGC TGG AAG GAA TAT AAA ATG GGT TTT

Leu Asp Phe Gln Arg Gly Trp Lys Glu Tyr Lys Met Gly Phe Gly Asn CCC TCC GGT GAA TAT TGG CTG GGG AAT GAG TTT ATT TTT GCC ATT

Pro Ser Gly Glu Tyr Trp Leu Gly Asn Glu Phe Ile Phe Ala Ile Thr AGT CAG AGG CAG TAC ATG CTA AGA ATT GAG TTA ATG GAC TGG

Ser Gin Arg Gin Tyr Met Leu Arg Ile Glu Leu Met Asp Trp Glu Gly AAC CGA GCC TAT TCA'GAG TAT GAC AGA TTC CAC ATA GGA AAT

Asn Arg Ala Tyr,Ber Gln Tyr Asp Arg Phe His Ile Gly Asn Glu Lys CAA AAC TAT AGG TTG TAT TTA AAA GGT CAC ACT GGG ACA GCA

Gln Asn Tyr Arg Leu Tyr Leu Lys Gly His Thr Gly Thr Ala Gly Lys CAG AGC AGC CTG ATC TTA CAC GGT GCT GAT TTC AGC ACT AAA GAT

Gln Ser Ser Leu Ile Leu His Gly Ala Asp Phe Ser Thr Lys Asp Ala GAT AAT GAC AAC TGT ATG TGC AAA TGT GCC CTC ATG TTA ACA GGA
GGA 1647 ' Asp Asn Asp Asn Cys Met Cys Lys Cys Ala Leu Met Leu Thr Gly Gly TGG TGG TTT GAT GCT TGT GGC CCC TCC AAT CTA AAT GGA ATG TTC

Trp Trp Phe Asp Ala Cys Gly Pro Ser Asn Leu Asn Gly Met Phe Tyr ACT GCG GGA CAA AAC CAT GGA AAA CTG AAT GGG ATA AAG TGG
CAC TAC 1743 1' Thr Ala Gly Gln Asn His Gly Lys Leu Asn Gly Ile Lys Trp His Tyr TTC AAA GGG CCC AGT TAC TCC TTA CGT TCC ACA ACT ATG ATG ATT

Phe Lys Gly Pro Ser Tyr Ser Leu Arg Ser Thr Thr Met Met Ile Arg CCT TTA GAT TTT TGA AAG CGCA ATGTCAGAAG CGATTATGAA

Pro Leu Asp Phe CGGAGAAGCT GCCAGGTGAG AAACTGTTTG AAAACTTCAG

CTTCCAGCAA TAAGTGGTAG TTATGTGAAG TCACCAAGGT

CCGTTTGAGT TCACAAGAGT CTCTACTTGG GGTGACAGTG

AAAACTCCAC TGACTGTCGG GCTTTAAAAA GGGAAGAAAC

AAACTACTAC TGGACCTTAT TTTGGAACTA TGGTAGCCAG

(2) INFORMATION FOR SEQ ID NO:2:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 498 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (v) FRAGMENT TYPE: internal (ix) FEATURE:

(A) NAME/KEY: Human TIE-2 ligand 1 (B) LOCATION: 1...498 (D) OTHER INFORMATION: from clone gt10 encoding htie-2 ligand 1 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:

Met Thr Val Phe Leu Ser Phe Ala Phe Leu Ala Ala Ile Leu Thr His Ile Gly Cys Ser Asn Gin Arg Arg Ser Pro Glu Asn Ser Gly Arg Arg Tyr Asn Arg Ile Gln His Gly Gln Cys Ala Tyr Thr Phe Ile Leu Pro Glu His Asp Gly Asn Cys Arg Glu Ser Thr Thr Asp Gin Tyr Asn Thr Asn Ala Leu Gln Arg Asp Ala Pro His Val Glu Pro Asp Phe Ser Ser Gln Lys Leu Gin His Leu Glu His Val Met Glu Asn Tyr Thr Gln Trp Leu Gln Lys Leu Glu Asn Tyr Ile Val Glu Asn Met Lys Ser Glu Met Ala Gln Ile Gln Gln Asn Ala Val Gin Asn His Thr Ala Thr Met Leu Glu Ile Gly Thr Ser Leu Leu Ser Gin Thr Ala Glu Gln Thr Arg Lys Leu Thr Asp Val Glu Thr Gln Val Leu Asn Gln Thr Ser Arg Leu Glu Ile Gln Leu Leu Glu Asn Ser Leu Ser Thr Tyr Lys Leu Glu Lys Gln Leu Leu Gln Gln Thr Asn Glu Ile Leu Lys Ile His Glu Lys Asn Ser Leu Leu Glu His Lys Ile Leu Glu Met Glu Gly Lys His Lys Glu Glu Leu Asp Thr Leu Lys Glu Glu Lys Glu Asn Leu Gln Gly Leu Val Thr Arg Gln Thr Tyr Ile Ile Gln Glu Leu Glu Lys Gln Leu Asn Arg Ala Thr Thr Asn Asn Ser Val Leu Gin Lys Gln Gln Leu Glu Leu Met Asp Thr Val His Asn Leu Val Asn Leu Cys Thr Lys Glu Gly Val Leu Leu Lys Gly Gly Lys Arg Glu Glu Glu Lys Pro Phe Arg Asp Cys Ala Asp Val Tyr Gln Ala Gly Phe Asn Lys Ser Gly Ile Tyr Thr Ile Tyr Ile Asn Asn Met Pro Glu Pro Lys Lys Val Phe Cys Asn Met Asp Val Asn Gly Gly Gly Trp Thr Val Ile Gln His Arg Glu Asp Gly Ser Leu Asp Phe Gln Arg Gly Trp Lys Glu Tyr Lys Met Gly Phe Gly Asn Pro Ser Gly Glu Tyr Trp Leu Gly Asn Glu Phe Ile Phe Ala Ile Thr Ser Gln Arg Gln Tyr Met Leu Arg Ile Glu Leu Met Asp Trp Glu Gly Asn Arg Ala Tyr Ser Gln Tyr Asp Arg Phe His Ile Gly Asn Glu Lys Gln Asn Tyr Arg Leu Tyr Leu Lys Gly His Thr Gly Thr Ala Gly Lys Gln Ser Ser Leu Ile Leu His Gly Ala Asp Phe Ser Thr Lys Asp Ala Asp Asn Asp Asn Cys Met Cys Lys Cys Ala Leu Met Leu Thr Gly Gly Trp Trp Phe Asp Ala Cys Gly Pro Ser Asn Leu Asn Gly Met Phe Tyr Thr Ala Gly Gin Asn His Gly Lys Leu Asn Gly Ile Lys Trp His Tyr Phe Lys Gly Pro Ser Tyr Ser Leu Arg Ser Thr Thr Met Met Ile Arg Pro Leu Asp Phe (2) INFORMATION FOR SEQ ID NO:3:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 2146 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA
(ix) FEATURE:

(A) NAME/KEY: Coding Sequence (B) LOCATION: 310...1800 (D) OTHER INFORMATION:

(A) NAME/KEY: Human TIE-2 ligand I
(B) LOCATION: 1...2146 (D) OTHER INFORMATION: from T98G clone (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3:
CAGCTGACTC AGGCAGGCTC CATGCTGAAC GGTCACACAG ' GCTACTATGC AATAAATATC TCAAGTTTTA ACGAAGAAAA

AAAATTTTAA AATTTTAGAA CAAAGCTAAC AAATGGCTAG

AACGCTTTCT TTGAGGGGGA AAGAGTCAAA CAAACAAGCA

CTAGTTTTAG AGGTCAGAAG AAAGGAGCAA GTTTTGCGAG

GGCAGTACA ATG ACA GTT TTC CTT TCC TTT GCT TTC CTC GCT GCC

Met Thr Val Phe Leu Ser Phe Ala Phe Leu Ala Ala Ile Leu ACT CAC ATA GGG TGC AGC AAT CAG CGC CGA AGT CCA GAA AAC

Thr His Ile Gly Cys Ser Asn Gln Arg Arg Ser Pro Glu Asn Ser Gly AGA AGA TAT AAC CGG ATT CAA CAT GGG CAA TGT GCC TAC ACT TTC

Arg Arg Tyr Asn Arg Iie Gln His Gly Gln Cys Ala Tyr Thr Phe Ile CTT CCA GAA CAC GAT GGC AAC TGT CGT GAG AGT ACG ACA GAC

Leu Pro Glu His Asp Gly Asn Cys Arg Glu Ser Thr Thr Asp Gin Tyr AAC ACA AAC GCT CTG CAG AGA GAT GCT CCA CAC GTG GAA CCG

Asn Thr Asn Ala Leu Gln Arg Asp Ala Pro His Val Glu Pro Asp Phe TCT TCC CAG AAA CTT CAA CAT CTG GAF. CAT GTG ATG GAA AAT TAT

Ser Ser Gin Lys Leu Gin His Leu Glu His Val Met Glu Asn Tyr Thr CAG TGG CTG CAA AAA CTT GAG AAT TAC ATT GTG GAA AAC ATG

Gln Trp Leu Gln Lys Leu Glu Asn Tyr Ile Val Glu'~sn Met Lys Ser GAG ATG GCC CAG ATA CAG CAG AAT GCA GTT CAG AAC CAC ACG

Glu Met Ala Gin Ile Gln Gln Asn Ala Val Gln Asn His Thr Ala Thr ATG CTG GAG ATA GGA ACC AGC CTC CTC TCT CAG ACT GCA GAG

Met Leu Glu Ile Gly Thr Ser Leu Leu Ser Gln Thr Ala Glu Gln Thr AGA AAG CTG ACA GAT GTT GAG ACC CAG GTA CTA AAT CAA ACT TCT

Arg Lys Leu Thr Asp Val Glu Thr Gin Val Leu Asn Gln Thr Ser Arg CTT GAG ATA CAG CTG CTG GAG AAT TCA TTA TCC ACC TAC AAG CTA

Leu Glu Ile Gln Leu Leu Glu Asn Ser Leu Ser Thr Tyr Lys Leu Glu 160 165 '170 AAG CAA CTT CTT CAA CAG ACA AAT GAA ATC TTG AAG ATC CAT GAA

Lys Gln Leu Leu Gln Gln Thr Asn Glu Ile Leu Lys Ile His Glu Lys AAC AGT TTA TTA GAA CAT AAA ATC TTA GAA ATG GAA GGA AAA

Asn Ser Leu Leu Glu His Lys Ile Leu Glu Met Glu Gly Lys His Lys GAA GAG TTG GAC ACC TTA AAG GAA GAG AAA GAG AAC CTT CAA

Glu Glu Leu Asp Thr Leu Lys Glu Glu Lys Glu Asn Leu Gln Gly Leu GTT ACT CGT CAA ACA TAT ATA ATC CAG GAG CTG GAA AAG CAA TTA

Val Thr Arg Gin Thr Tyr Ile Ile Gin Giu Leu Glu Lys Gin Leu Asn AGA GCT ACC ACC AAC AAC AGT GTC CTT CAG AAG CAG CAA CTG

Arg Ala Thr Thr Asn Asn Ser Val Leu Gin Lys Gln Gln Leu Glu Leu ATG GAC ACA GTC CAC AAC CTT GTC AAT CTT TGC ACT AAA GAA GTT

Met Asp Thr Val His Asn Leu Val Asn Leu Cys Thr Lys Glu Val Leu CTA AAG GGA GGA AAA AGA GAG GAA GAG AAA CCA TTT AGA GAC

Leu Lys Gly Gly Lys Arg Glu Glu Glu Lys Pro Phe Arg Asp Cys Ala GAT GTA TAT CAA GCT GGT TTT AAT AAA AGT GGA ATC TAC ACT ATT

Asp Val Tyr Gln Ala Gly Phe Asn Lys Ser Gly Ile Tyr Thr Ile Tyr ATT AAT AAT ATG CCA GAA CCC AAA AAG GTG TTT TGC AAT ATG GAT

Ile Asn Asn Met Pro Glu Pro Lys Lys Val Phe Cys Asn Met Asp Val AAT GGG GGA GGT TGG ACT GTA ATA CAA CAT CGT GAA GAT GGA

Asn Gly Gly Gly Trp Thr Val Ile Gln His Arg Glu Asp Gly Ser Leu GAT TTC CAA AGA GGC TGG AAG GAA TAT AAA ATG GGT TTT GGA
AAT CCC 1359 '"
Asp Phe Gln Arg Gly Trp Lys Glu Tyr Lys Met Gly Phe Gly Asn Pro TCC GGT GAA TAT TGG CTG GGG AAT GAG TTT ATT TTT GCC ATT ACC
AGT 1407 .1 Ser Giy Glu Tyr Trp Leu Gly Asn Glu Phe Ile Phe Ala Ile Thr Ser CAG AGG CAG TAC ATG CTA AGA ATT GAG TTA ATG GAC TGG GAA

Gln Arg Gln Tyr Met Leu Arg Ile Glu Leu Met Asp Trp Glu Gly Asn CGA GCC TAT TCA CAG TAT GAC AGA TTC CAC ATA GGA AAT GAA

Arg Ala Tyr Ser Gln Tyr Asp Arg Phe His Ile Gly Asn Glu Lys Gln AAC TAT AGG TTG TAT TTA AAA GGT CAC ACT GGG ACA GCA GGA

Asn Tyr Arg Leu Tyr Leu Lys Gly His Thr Gly Thr Ala.Gly Lys Gln AGC AGC CTG ATC TTA CAC GGT GCT GAT TTC AGC ACT AAA GAT GCT

Ser Ser Leu Ile Leu His Gly Ala Asp Phe Ser Thr Lys Asp Ala Asp AAT GAC AAC TGT ATG TGC AAA TGT GCC CTC ATG TTA ACA GGA GGA

Asn Asp Asn Cys Met Cys Lys Cys Ala Leu Met Leu Thr Gly Gly Trp TGG TTT GAT GCT TGT GGC CCC TCC AAT CTA AAT GGA ATG TTC TAT

Trp Phe Asp Ala Cys Gly Pro Ser Asn Leu Asn Gly Met Phe Tyr Thr GCG GGA CAA AAC CAT CGA AAA CTG AAT GGG ATA AAG TGG CAC

Ala Gly Gln Asn His Arg Lys Leu Asn Gly Ile Lys Trp His Tyr Phe AAA GGG CCC AGT TAC TCC TTA CGT TCC ACA ACT ATG ATG ATT CGA

Lys Gly Pro Ser Tyr Ser Leu Arg Ser Thr Thr Met Met Ile Arg Pro TTA GAT TTT TGA AAGCGCA ATGTCAGAAG CGATTATGAA

Leu Asp Phe GAAGCTGCCA GGTGAGAAAC TGTTTGAAAA CTTCAGAAGC
AAACP.ATATT GTCTCCCTTC 1909 Mq4, CACCAATAAG TGGTAGTTAT GTGAAGTCAC CAAGGTTCTT

TTGAGTTCAC AAGAGTCTCT ACTTGGGGTG ACAGTGCTCA

CTCCACTGAC TGTCGGGCTT TAAAAAGGGA AGAAACTGCT

TACTACTGGA CCTTATTTTG GAACTATGGT AGCCAGATGA

(2) INFORMATION FOR SEQ ID NO:4:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 497 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (v) FRAGMENT TYPE: internal (ix) FEATURE:

(A) NAME/KEY: Human TIE-2 ligand 1 (B) LOCATION: 1...2146 (D) OTHER INFORMATION: from T98G clone (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4: Met Thr Val Phe Leu Ser Phe Ala Phe Leu Ala Ala Ile Leu Thr His Ile Gly Cys Ser Asn Gln Arg Arg Ser Pro Glu Asn Ser Gly Arg Arg Tyr Asn Arg Ile Gln His Gly Gln Cys Ala Tyr Thr Phe Ile Leu Pro Glu His Asp Gly Asn Cys Arg Glu Ser Thr Thr Asp Gln Tyr Asn Thr Asn Ala Leu Gin Arg Asp Ala Pro His Val Glu Pro Asp Phe Ser Ser Gln Lys Leu Gln His Leu Glu His Val Met Glu Asn Tyr Thr Gln Trp Leu Gln Lys Leu Glu Asn Tyr Ile Val Glu Asn Met Lys Ser Glu Met Ala Gln Ile Gln Gln Asn Ala Val Gln Asn His Thr Ala Thr Met Leu Glu Ile Gly Thr Ser Leu Leu Ser Gln Thr Ala Giu Gin Thr Arg Lys Leu Thr Asp Val Glu Thr Gln Val Leu Asn Gln Thr Ser Arg Leu Glu Ile Gln Leu Leu Glu Asn Ser Leu Ser Thr Tyr Lys Leu Giu Lys Gln Leu Leu Gin Gln Thr Asn Glu Ile Leu Lys Ile His Glu Lys Asn Ser Leu Leu Glu His Lys Ile Leu Glu Met Glu Gly Lys His Lys Glu Glu Leu Asp Thr Leu Lys Glu Glu Lys Glu Asn Leu Gln Gly Leu Val Thr Arg Gin Thr Tyr Ile Ile Gln Glu Leu Glu Lys Gln Leu Asn Arg Ala Thr Thr Asn Asn Ser Val Leu Gln Lys Gin Gln Leu Giu Leu Met Asp Thr Val His Asn Leu Val Asn Leu Cys Thr Lys Glu Val Leu Leu Lys Gly Gly Lys Arg Glu Glu Glu Lys Pro Phe Arg Asp Cys Ala Asp Val Tyr Gin Ala Gly Phe Asn Lys Ser Gly Ile Tyr Thr Ile Tyr Ile Asn Asn Met Pro Glu Pro Lys Lys Val Phe Cys Asn Met Asp Val Asn Gly Gly Gly Trp Thr Val Ile Gln His Arg Glu Asp Gly Ser Leu Asp Phe Gln Arg Gly Trp Lys Glu Tyr Lys Met Gly Phe Gly Asn Pro Ser Gly Glu Tyr Trp Leu,Gly Asn Glu Phe Ile Phe Ala Ile Thr Ser Gln Arg Gln Tyr Met Leu Arg Ile Glu Leu Met Asp Trp Glu Gly Asn Arg Ala Tyr Ser Gln Tyr Asp Arg Phe His Ile Gly Asn Glu Lys Gin Asn Tyr Arg Leu Tyr Leu Lys Gly His Thr Gly Thr Ala GlyHLys Gln Ser Ser Leu Ile Leu His Gly Ala Asp Phe Ser Thr Lys Asp Ala Asp Asn Asp Asn Cys Met Cys Lys Cys Ala Leu Met Leu Thr Gly Gly Trp Trp Phe Asp Ala Cys Gly Pro Ser Asn Leu Asn Gly Met Phe Tyr Thr Ala Gly Gln Asn His Arg,'Lys Leu Asn Gly Ile Lys Trp His Tyr Ph( Lys Gly Pro Ser Tyr Ser Leu Arg Ser Thr Thr Met Met Ile Arg Pro L'eu Asp Phe (2) INFORMATION FOR SEQ ID NO:5:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 2282 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA
(ix) FEATURE:

(A) NAME/KEY: Coding Sequence (B) LOCATION: 357...1844 (D) OTHER INFORMATION:

(A) NAME/KEY: Human TIE-2 ligand 2 (B) LOCATION: 1...2282 (D) OTHER INFORMATION: from clone pBluescript KS
encoding human TIE 2 ligand 2 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5:

GAATTCCTGG GTTGGTGTTT ATCTCCTCCC AGCCTTGAGG

TCTGGGGAGA GAGGAACAAA GGACCGTGAA AGCTGCTCTG

CCAAGTGAGC AGGACTGTTC TTCCCACTGC AATCTGACAG

AACACAGCAG TAAAAACCAG GTTTGCTACT GGAAAP.AGAG

ACGGACCCAG CCATGGCAGC GTAGCAGCCC TGCGTTTCAG

TGGACGTGTG TTTGCCCTCA AGTTTGCTAA GCTGCTGGTT

Met i TGG CAG ATT GTT TTC TTT ACT CTG AGC TGT GAT CTT GTC TTG GCC

Trp Gin Ile Val Phe Phe Thr Leu Ser Cys Asp Leu Val Leu Ala Ala , ;9'p,=

GCC TAT AAC AAC TTT CGG AAG AGC ATG GAC AGC ATA GGA AAG
AAG CAA 455 ' Ala Tyr Asn Asn Phe Arg Lys Ser Met Asp Ser Ile Gly Lys Lys Gln TAT CAG GTC CAG CAT GGG TCC TGC AGC TAC ACT TTC CTC CTG CCA

Tyr Gln Val Gln His Gly Ser Cys Ser Tyr Thr Phe Leu Leu Pro Glu ATG GAC AAC TGC CGC TCT TCC TCC AGC CCC TAC GTG TCC AAT GCT

Met Asp Asn Cys Arg Ser Ser Ser Ser Pro Tyr Val Ser Asn Ala Val CAG AGG GAC GCG CCG CTC GAA TAC GAT GAC TCG GTG CAG AGG

Gln Arg Asp Ala' Pro Leu Glu Tyr Asp Asp Ser Val Gln Ar=g Leu Gln GTG CTG GAG AAC ATC ATG GAA AAC AAC ACT CAG TGG CTA ATG

Val Leu Glu Asn Ile Met Glu Asn Asn Thr Gln Trp Leu Met Lys Leu GAG AAT TAT ATC CAG GAC AAC ATG AAG AAA GAA ATG GTA GAG

Glu Asn Tyr Ile Gln Asp Asn Met Lys Lys Glu Met Val Glu Ile Gln CAG AAT GCA GTA CAG AAC CAG ACG GCT GTG ATG ATA GAA ATA

Gln Asn Ala Val Gin Asn Gln Thr Ala Val Met Ile Glu Ile Gly Thr AAC CTG TTG AAC CAA ACA GCT GAG CAA ACG CGG AAG TTA ACT

Asn Leu Leu Asn Gln Thr Ala Glu Gln Thr Arg Lys Leu Thr Asp Val GAA GCC CAA GTA TTA AAT CAG ACC ACG AGA CTT GAA CTT CAG CTC

Glu Ala Gln Val Leu Asn Gln Thr Thr Arg Leu Glu Leu Gln Leu Leu GAA CAC TCC CTC TCG ACA AAC AAA TTG GAA AAA CAG ATT TTG

Glu His Ser Leu Ser Thr Asn Lys Leu Glu Lys Gln Ile Leu Asp Gln ACC AGT GAA ATA AAC AAA TTG CAA GAT AAG AAC AGT TTC CTA

Thr Ser Glu Ile Asn Lys Leu Gln Asp Lys Asn Ser Phe Leu Glu Lys AAG GTG CTA GCT ATG GAA GAC AAG CAC ATC ATC CAA CTA CAG

Lys Val Leu Ala Met Glu Asp Lys His Ile Ile Gln Leu Gln Ser Ile AAA GAA GAG AAA GAT CAG CTA CAG GTG TTA GTA TCC AAG CAA

Lys Glu Glu Lys Asp Gln Leu Gln Val Leu Val Ser Lys Gin Asn Ser ATC ATT GAA GAA CTA GAA AAA AAA ATA GTG ACT GCC ACG GTG

Ile Ile Glu Glu Leu Glu Lys Lys Ile Val Thr Ala Thr Val Asn Asn TCA GTT CTT CAA AAG CAG CAA CAT GAT CTC ATG GAG ACA GTT AAT

Ser Val Leu Gin Lys Gln Gln His Asp Leu Met Glu Thr Val Asn Asn TTA CTG ACT ATG ATG TCC ACA TCA AAC TCA GCT AAG GAC CCC ACT

Leu Leu Thr Met Met Ser Thr Ser Asn Ser Ala Lys Asp Pro Thr Val GCT AAA GAA GAA CAA ATC AGC TTC AGA GAC TGT GCT GAA GTA
TTC AAA 1223 1 , Ala Lys Glu Glu Gln Ile Ser Phe Arg Asp Cys Ala Glu Val Phe Lys TCA GGA CAC ACC ACA AAT GGC ATC TAC ACG TTA ACA TTC CCT AAT

Ser Gly His Thr Thr Asn Gly Ile Tyr Thr Leu Thr Phe Pro Asn Ser ACA GAA GAG ATC AAG GCC TAC TGT GAC ATG GAA GCT GGA GGA

Thr Glu Glu Ile Lys Ala Tyr Cys Asp Met Glu Ala Gly Gly Gly Gly TGG ACA ATT ATT CAG CGA CGT GAG GAT GGC AGC GTT GAT TTT CAG

Trp Thr Ile Ile Gln Arg Arg Glu Asp Gly Ser Val Asp Phe Gln Arg ACT TGG AAA GAA TAT AAA GTG GGA TTT GGT AAC CCT TCA GGA

Thr Trp Lys Glu Tyr Lys Val Gly Phe Gly Asn Pro Ser Gly Glu Tyr TGG CTG GGA AAT GAG TTT GTT TCG CAA CTG ACT AAT CAG CAA CGC

Trp Leu Gly Asn Glu Phe Val Ser Gln Leu Thr Asn Gln Gln Arg Tyr GTG CTT AAA ATA CAC CTT AAA GAC TGG GAA GGG AAT GAG GCT

Val Leu Lys Ile His Leu Lys Asp Trp Glu Gly Asn Glu Ala Tyr Ser TTG TAT GAA CAT TTC TAT CTC TCA AGT GAA GAA CTC AAT TAT AGG

Leu Tyr Glu His Phe Tyr Leu Ser Ser Glu Glu Leu Asn Tyr Arg Ile CAC CTT AAA GGA CTT ACA GGG ACA GCC GGC AAA ATA AGC AGC

His Leu Lys Gly Leu Thr Gly Thr Ala Gly Lys Ile Ser Ser Ile Ser CAA CCA GGA AAT GAT TTT AGC ACA AAG GAT GGA GAC AAC GAC

Gin Pro Gly Asn Asp Phe Ser Thr Lys Asp Giy Asp Asn Asp Lys Cys ATT TGC AAA TGT TCA CAA ATG CTA ACA GGA GGC TGG TGG TTT GAT

Ile Cys Lys Cys Ser Gln Met Leu Thr Gly Gly Trp Trp Phe Asp Ala TGT GGT CCT TCC AAC TTG AAC GGA ATG TAC TAT CCA CAG AGG CAG
AAC 1751 ' Cys Gly Pro Ser Asn Leu Asn Gly Met Tyr Tyr Pro Gin Arg Gln Asn ACA AAT AAG TTC AAC GGC ATT AAA TGG TAC TAC TGG AAA GGC

Thr Asn Lys Phe Asn Gly Ile Lys Trp Tyr Tyr Trp Lys Gly Ser Gly TAT TCG CTC AAG GCC ACA ACC ATG ATG ATC CGA CCA GCA GAT TTC

Tyr Ser Leu Lys Ala Thr Thr Met Met Ile Arg Pro Ala Asp Phe ATCCCAGTCC ACCTGAGGAA CTGTCTCGAA CTATTTTCAA
AGACTTAAGC CCAGT(~CACT 1909 GAAAGTCACG GCTGCGCACT GTGTCCTCTT CCACCACAGA

CGGGACCCAC ATGCTCCAGA TTAGAGCCTG TAAACTTTAT

AACGGACCAA AGCAAGACCC TAAACATCCA TAATTGTGAT

AGATGAACCC GAGGCTGAGA ATCAGACTGA CAGTTTACAG

AATGTTATGT GCAAGTTTAT CAGTAAATAA CTGGAAAACA

ACAGATCATC TTGGAACTGC ATTCTTCTGA GCACTGTTTA

(2) INFORMATION FOR SEQ ID NO:6:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 496 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (v) FRAGMENT TYPE: internal (ix) FEATURE:

(A) NAME/KEY: Human TIE-2 ligand 2 (B) LOCATION: 1...496 (D) OTHER INFORMATION: from clone pBluescript KS
encoding human TIE 2 ligand 2 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6:

Met Trp Gln Ile Val Phe Phe Thr Leu Ser Cys Asp Leu Val Leu Ala Ala Ala Tyr Asn Asn Phe Arg Lys Ser Met Asp Ser Ile Gly Lys Lys Gln Tyr Gln Val Gln His Gly Ser Cys Ser Tyr Thr Phe Leu Leu Pro 35 40 . 45 Glu Met Asp Asn Cys Arg Ser Ser Ser Ser Pro Tyr Val Ser Asn Ala Val Gln Arg Asp Ala Pro Leu Glu Tyr Asp Asp Ser Val Gin Arg Leu Gln Val Leu Glu Asn Ile Met Glu Asn Asn Thr Gln Trp Leu Met Lys Leu Glu Asn Tyr Ile Gln Asp Asn Met Lys Lys Glu Met Val Glu Ile Gln Gln Asn Ala Val Gin Asn Gln Thr Ala Val Met Ile Glu Ile Gly Thr Asn Leu Leu Asn Gin Thr Ala Glu Gln Thr Arg Lys Leu Thr Asp 130 135 140', Val Glu Ala Gln Val Leu Asn Gln Thr Thr Arg Leu Glu Leu Gln Leu Leu Glu His Ser Leu Ser Thr Asn Lys Leu Glu Lys Gln Ile Leu Asp Gln Thr Ser Glu Ile Asn Lys Leu G1n Asp Lys Asn Ser Phe Leu Glu Lys Lys Val Leu Ala Met Glu Asp Lys His Ile Ile Gln Leu Gln Ser Ile Lys Glu Glu Lys Asp Gln Leu Gln Val Leu Val Ser Lys Gln Asn Ser Ile Ile Glu Glu Leu Glu Lys Lys lie Val Thr Ala Thr Val Asn Asn Ser Val Leu Gln Lys Gln Gln His Asp Leu Met Glu Thr Val Asn Asn Leu Leu Thr Met Met Ser Thr Ser Asn Ser Ala Lys Asp,Pro Thr Val Ala Lys Glu Glu Gln Ile Ser Phe Arg Asp Cys Ala Glu Val Phe Lys Ser Gly His Thr Thr Asn Gly Ile Tyr Thr Leu Thr Phe Pro Asn Ser Thr Glu Glu Ile Lys Ala Tyr Cys Asp Met Glu Ala Gly Gly Gly Gly Trp Thr Ile Ile Gln Arg Arg Glu Asp Gly Ser Val Asp Phe Gln Arg Thr Trp Lys Glu Tyr Lys Val Gly Phe Gly Asn Pro Ser Gly Glu Tyr Trp Leu Gly Asn Glu Phe Val Ser Gln Leu Thr Asn Gln Gln Arg Tyr Val Leu Lys Ile His Leu Lys Asp Trp Glu Gly Asn Glu Ala Tyr Ser Leu Tyr Glu His Phe Tyr Leu Ser Ser Glu Glu Leu Asn Tyr Arg Ile His Leu Lys Gly Leu Thr Gly Thr Ala Gly Lys Ile Ser Ser Ile Ser Gin Pro Gly Asn Asp Phe Ser Thr Lys Asp Gly Asp Asn Asp Lys Cys Ile Cys Lys Cys Ser Gln Met Leu Thr Gly Gly Trp Trp Phe Asp Ala Cys Gly Pro Ser Asn Leu Asn Gly Met Tyr Tyr Pro Gln Arg Gln Asn Thr Asn Lys Phe Asn Gly Ile Lys Trp Tyr Tyr Trp Lys Gly Ser Gly Tyr Ser Leu Lys Ala Thr Thr Met Met Ile Arg Pro Ala Asp Phe (2) INFORMATION FOR SEQ ID NO:7:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 478 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (ix) FEATURE:

(A) NAME/KEY: Mature TLI protein (B) LOCATION: 1...478 (D) OTHER INFORMATION:

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:7:

Asn Gln Arg Arg Ser Pro Glu Asn Ser Gly Arg Arg Tyr Asn Arg Ile Gln His Gly Gln Cys Ala Tyr Thr Phe Ile Leu Pro Glu His Asp Gly Asn Cys Arg Glu Ser Thr Thr Asp Gln Tyr Asn Thr Asn Ala Leu Gln Arg Asp Ala Pro His Vai Glu Pro Asp Phe Ser Ser Gln Lys Leu Gln His Leu Glu His Val Met Glu Asn Tyr Thr Gln Trp Leu Gln Lys Leu 65 70 75 , 80 Glu Asn Tyr Ile Val Glu Asn Met Lys Ser Glu Met Ala Gln Ile Gln Gln Asn Ala Val Gin Asn His Thr Ala Thr Met Leu Glu Ile Gly Thr Ser Leu Leu Ser Gln Thr Ala Glu Gln Thr Ai~g Lys Leu Thr Asp Val Glu Thr Gln Val Leu Asn Gln Thr Ser Arg Leu Glu Ile Gln Leu Leu Glu Asn Ser Leu Ser Thr Tyr Lys Leu Glu Lys Gln Leu Leu Gln Gln Thr Asn Glu Ile Leu Lys Ile His Glu Lys Asn Ser Leu Leu Glu His Lys Ile Leu Glu Met Glu Gly Lys His Lys Glu Glu Leu Asp Thr Leu Lys Glu Glu Lys Glu Asn Leu Gln Gly Leu Val Thr Arg Gln Thr Tyr Ile Ile Gln Glu Leu Glu Lys Gln Leu Asn Arg Ala Thr Thr Asn Asn Ser Val Leu Gln Lys Gin Gln Leu Glu Leu Met Asp Thr Val His Asn Leu Val Asn Leu Cys Thr Lys Glu Gly Val Leu Leu Lys Giy Gly Lys Arg Glu Glu Glu Lys Pro Phe Arg Asp Cys Ala Asp Val Tyr Gln Ala 'Gly Phe Asn Lys Ser Gly Ile Tyr Thr Ile Tyr Ile Asn Asn Met Pro Glu Pro Lys Lys Val Phe Cys Asn Met Asp Val Asn Gly Gly Gly Trp Thr Val Ile Gln His Arg Glu Asp Gly Ser Leu Asp Phe Gln Arg Cly Trp Lys Glu Tyr Lys Met Gly Phe Gly Asn Pro Ser Gly Glu Tyr Trp Leu Gly Asn Glu Phe Ile Phe Ala Ile Thr Ser Gln Arg Gln Tyr Met Leu Arg Ile Glu Leu Met Asp Trp Glu Gly Asn Arg Ala Tyr Ser Gln Tyr Asp Arg Phe His Ile Gly Asn Glu Lys Gln Asn Tyr Arg Leu Tyr Leu Lys Gly His Thr Gly Thr Ala Gly Lys Gln Ser Ser Leu Ile Leu His Gly Ala Asp Phe Ser Thr Lys Asp Ala Asp Asn Asp Asn Cys Met Cys Lys Cys Ala Leu Met Leu Thr Gly Gly Trp Trp Phe Asp Ala Cys Gly Pro Ser Asn Leu Asn Gly Met Phe Tyr Thr Ala Gly Gin Asn His Gly Lys Leu Asn Gly Ile Lys Trp His Tyr Phe Lys Gly Pro Ser Tyr Ser Leu Arg Ser Thr Thr Met Met Ile Arg Pro Leu Asp Phe (2) INFORMATION FOR SEQ ID NO:8:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 480_amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (ix) FEATURE:

(A) NAME/KEY: Mature TL2 protein (B) LOCATION: 1...480 (D) OTHER INFORMATION:

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:8:

Ala Ala Tyr Asn Asn Phe Arg Lys Ser Met Asp Ser Ile Gly Lys Lys Gln Tyr Gln Val Gln His Gly Ser Cys Ser Tyr Thr Phe Leu Leu Pro Glu Met Asp Asn Cys Arg Ser Ser Ser Ser Pro Tyr Val Ser Asn Ala 35 ' 40 45 Val Gln Arg Asp Ala Pro Leu Glu Tyr Asp Asp Ser Val Gln Arg Leu 50 55 60 ' Gln Val Leu Glu Asn Ile Met Glu Asn Asn Thr Gln Trp Leu Met Lys Leu Glu Asn Tyr Ile Gln Asp Asn Met Lys Lys Glu Met Val Glu Ile Gln Gln Asn Ala Val Gln Asn Gln Thr Ala Val Met Ile Glu Ile Gly Thr Asn Leu Leu Asn Gln Thr Ala Glu Gln Thr Arg Lys Leu Thr Asp Val Glu Ala Gln Val Leu Asn Gln Thr Thr Arg Leu Glu Leu Gln Leu Leu Glu His Ser Leu Ser Thr Asn Lys Leu Glu Lys Gln Ile Leu Asp Gln Thr Ser Glu Ile Asn Lys Leu Gln Asp Lys Asn Ser Phe Leu Glu Lys Lys Val Leu Ala Met Glu Asp Lys His Ile Ile Gln Leu Gln Ser Ile Lys Glu Glu Lys Asp Gln Leu Gln Val Leu Val Ser Lys Gln Asn Ser"Ile Ile Glu Glu Leu Glu Lys Lys Ile Val Thr Ala Thr Val Asn Asn Ser Val Leu Gln Lys Gln Gln His Asp Leu Met Glu Thr Val Asn Asn Leu Leu Thr Met Met Ser Thr Ser Asn Ser Ala Lys Asp Pro Thr Val Ala Lys Glu Glu Gln Ile Ser Phe Arg Asp Cys Ala Glu Val Phe Lys Ser Gly His Thr Thr Asn Gly Ile Tyr Thr Leu Thr Phe Pro Asn Ser Thr Glu Glu Ile Lys Ala Tyr Cys Asp Met Glu Ala Gly Gly Gly Gly Trp Thr Ile Ile Gln Arg Arg Glu Asp Gly Ser Val Asp Phe Gln Arg Thr Trp Lys Glu Tyr Lys Val Gly Phe Gly Asn Pro Ser Gly Glu Tyr Trp Leu Gly Asn Glu Phe Val Ser Gln Leu Thr Asn Gln Gln Arg Tyr Val Leu Lys Ile His Leu Lys Asp Trp Glu Gly Asn Glu Ala Tyr Ser Leu Tyr Glu His Phe Tyr Leu Ser Ser Glu Glu Leu Asn Tyr Arg Ile His Leu Lys Gly Leu Thr Giy Thr Ala Gly Lys Ile Ser Ser Ile Ser Gln Pro Gly Asn Asp Phe Ser Thr Lys Asp Gly Asp Asn Asp Lys Cys Ile Cys Lys Cys Ser Gln Met Leu Thr Gly Gly Trp Trp Phe Asp ..~y , Ala Cys Gly Pro Ser Asn Leu Asn Gly Met Tyr Tyr Pro Gln Arg Gln Asn Thr Asn Lys Phe Asn Gly Ile Lys Trp Tyr Tyr Trp Lys Gly Ser 450 ' 455 460 Gly Tyr Ser Leu Lys Ala Thr Thr Met Met Ile ArgPro Ala Asp Phe (2) INFORMATION FOR SEQ ID NO:9:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 1849 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA
(ix) FEATURE:

(A) NA~4E/KEY: Coding Sequence (B) LOCATION: 47...1573 (D) OTHER INFORMATION:

(A) NAME/KEY: TIE ligand-3 (B) LOCATION: 1...1849 (D) OTHER INFORMATION: The fibrinogen-like domain starts at position 929.
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:9:

CTGTCCTGGT ACCTGACAAG ACCACCTCAC CACCACTTGG TCTCAG

Met Leu Cys =CAG CCA GCT ATG CTA CTA GAT GGC CTC CTC CTG CTG GCC ACC ATG

Gin Pro Ala Met Leu Leu Asp Gly Leu Leu Leu Leu Ala Thr Met Ala GCA GCC CAG CAC AGA GGG CCA GAA GCC GGT GGG CAC CGC CAG

Ala Ala Gin His Arg Gly Pro Glu Ala Gly Gly His Arg Gln Ile His CAG GTC CGG CGT GGC CAG TGC AGC TAC ACC TTT GTG GTG CCG GAG

Gln Val Arg Arg Gly Gln Cys Ser Tyr Thr Phe Val Val Pro Glu Pro GAT ATC TGC CAG CTG GCG CCG ACA GCG GCG CCT GAG GCT TTG

Asp Ile Cys Gln Leu Ala Pro Thr Ala Ala Pro Glu Ala Leu Gly Gly TCC AAT AGC CTC CAG AGG GAC TTG CCT GCC TCG AGG CTG CAC CTA

Ser Asn Ser Leu Gln Arg Asp Leu Pro Ala Ser Arg Leu His Leu Thr GAC TGG CGA GCC CAG AGG GCC CAG CGG GCC CAG CGT GTG AGC

Asp Trp Arg Ala Gln Arg Ala Gin Arg Ala Gln Arg Val Ser Gln Leu GAG AAG ATA CTA GAG AAT AAC ACT CAG TGG CTG CTG AAG CTG

y,u Glu Lys Ile Leu Glu Asn Asn Thr Gln Trp Leu Leu Lys Leu Glu Gln TCC ATC AAG GTG AAC TTG AGG TCA CAC CTG GTG CAG,GCC CAG

Ser Ile Lys Val Asn Leu Arg Ser His Leu Val Gln Ala Gln Gln Asp ACA ATC CAG AAC CAG ACA ACT ACC ATG CTG GCA CTG GGT GCC

Thr Ile Gln Asn Gln Thr Thr Thr Met Leu Ala Leu Gly Ala Asn Leu ATG AAC CAG ACC AAA GCT CAG ACC CAC AAG CTG ACT GCT GTG

Met Asn Gln Thr Lys Ala Gln Thr His Lys Leu Thr Ala Val Glu Ala CAG GTC CTA AAC CAG ACA TTG CAC ATG AAG ACC CAA ATG CTG

Gln Val Leu Asn Gln Thr Leu His Met Lys Thr Gln Met Leu Gl,u Asn TCA CTG TCC ACC AAC AAG CTG GAG CGG CAG ATG CTG ATG CAG

Ser Leu Ser Thr Asn Lys Leu Glu Arg Gln Met Leu Met Gin Ser Arg GAG CTG CAG CGG CTG CAG GGT CGC AAC AGG GCC CTG GAG AGC

Glu Leu Gln Arg Leu Gin Gly Arg Asn Arg Ala Leu Glu Thr Arg Leu CAG GCA CTG GAA GCA CAA CAT CAG GCC CAG CTT AAC AGC CTC

=Gin Ala Leu Glu Ala Gln His Gin Ala Gin Leu Asn Ser Leu Gln Glu AAG AGG GAA CAA CTG CAC AGT CTC CTG GGC CAT CAG ACC GGG

Lys Arg Glu Gln Leu His Ser Leu Leu Gly His Gln Thr Gly Thr Leu GCT AAC CTG AAG CAC AAT CTG CAC GCT CTC AGC AGC AAT TCC AGC

Ala Asn Leu Lys His Asn Leu His Ala Leu Ser Ser Asn Ser Ser Ser CTG CAG CAG CAG CAG CAG CAA CTG ACG GAG TTT GTA CAG CGC

Leu Gln Gln Gln Gln Gln Gln Leu Thr Glu Phe Val Gln Arg Leu Val CGG ATT GTA GCC CAG GAC CAG CAT CCG GTT TCC TTA AAG ACA CCT

Arg Ile Val Ala Gln Asp GIn His Pro Val Ser Leu Lys Thr Pro Lys CCA GTG TTC CAG GAC TGT GCA GAG ATC AAG CGC TCC GGG GTT AAT

Pro Val Phe Gln Asp Cys Ala Glu lie Lys Arg Ser Gly Val Asn Thr AGC GGT GTC TAT ACC ATC TAT GAG ACC AAC ATG ACA AAG CCT CTC

Ser Gly Val Tyr Thr lie Tyr Glu Thr Asn Met Thr Lys Pro Leu Lvs . . - ,~

GTG TTC TGT GAC ATG GAG ACT GAT GGA GGT GGC TGG ACC CTC ATC

Val Phe Cys Asp Met Glu Thr Asp Gly Gly Gly Trp ',Thr Leu Ile Gln CAC CGG GAG GAT GGA AGC GTA AAT TTC CAG AGG ACC TGG GAA

His Arg Glu Asp Gly Ser Val Asn Phe Gln Arg Thr Trp Glu Glu Tyr AAA GAG GGT TTT GGT AAT GTG GCC AGA GAG CAC TGG CTG GGC

Lys Glu Gly Phe Gly Asn Val Ala Arg Glu HisTrp Leu Giy Asn Glu GCT GTG CAC CGC CTC ACC AGC AGA ACG GCC TAC TTG CTA CGC GTG

Ala Val His Arg,Leu Thr Ser Arg Thr Ala Tyr Leu Leu Arg Val Glu CTG CAT GAC TGG GAA GGC CGC CAG ACC TCC ATC CAG TAT GAG

Leu His Asp Trp Glu Gly Arg Gln Thr Ser Ile Gln Tyr Glu Asn Phe CAG CTG GGC AGC GAG AGG CAG CGG TAC AGC CTC TCT GTG AAT

Gin Leu Gly Ser Glu Arg Gln Arg Tyr Ser Leu Ser Val Asn Asp Ser AGC AGT TCA GCA GGG CGC AAG AAC AGC CTG GCT CCT CAG GGC

Ser Ser Ser Ala Gly Arg Lys Asn Ser Leu Ala Pro Gln Gly Thr Lys TTC AGC ACC AAA GAC ATG GAC AAT GAT AAC TGC ATG TGT AAA TGT

Phe Ser Thr Lys Asp Met Asp Asn Asp Asn Cys Met Cys Lys Cys Ala CAG ATG CTG TCT GGA GGG TGG TGG TTT GAT GCC TGT GGC CTC TCC

Gin Met Leu Ser Gly Gly Trp Trp Phe Asp Ala Cys Gly Leu Ser Asn CTC AAT GGC ATC TAC TAT TCA GTT CAT CAG CAC TTG CAC AAG ATC

Leu Asn Gly Ile Tyr Tyr Ser Val His Gln His Leu His Lys Ile Asn GGC ATC CGC TGG CAC TAC TTC CGA GGC CCC AGC TAC TCA CTG CAC

Gly Ile Arg Trp His Tyr Phe Arg Gly Pro Ser Tyr Ser Leu His Gly ACA CGC ATG ATG CTG AGG CCA ATG GGT GCC TGA CACACAG

Thr Arg Met Met Leu Arg Pro Met Gly Ala GATGCCGTAG GAGGATTCTC AACCCAGGTG ACTCTGTGCA

TCAGTGCCCA GGGCTCATCT TGACATTCTG GAACATCGGA

AATTACAAGA ATTCACCTGC CTCCCTGTTG CCCTCTAATT

AAGGCACCTG CCTCTGTTGG AACCATACTC TTTCCCCCTC

(2) INFORMATION FOR SEQ ID NO:10:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 509 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (v) FRAGMENT TYPE: internal (ix) FEATURE:

(A) NAME/KEY: TIE ligand-3 (B) LOCATION: 1...509 (D) OTHER INFORMATION:

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:10:

Met Leu Cys Gln Pro Ala Met Leu Leu Asp G1y,Leu Leu Leu Leu Ala Thr Met Ala Ala Ala Gln His Arg Gly Pro Glu Ala Gly Gly His Arg Gln Ile His Gln Val Arg Arg Gly Gln Cys Ser Tyr Thr Phe Val Val Pro Glu Pro Asp Ile Cys Gln Leu Ala Pro Thr Ala Ala Pro Glu Ala Leu Gly Gly Ser Asn Ser Leu Gln Arg Asp Leu Pro Ala Ser Arg Leu His Leu Thr Asp Trp Arg Ala Gln Arg Ala Gln Arg Ala G1n Arg Val Ser Gin Leu Glu Lys Ile Leu Glu Asn Asn Thr Gin Trp Leu Leu Lys Leu Glu Gln Ser Ile Lys Val Asn Leu Arg Ser His Leu Val Gln Ala Gln Gln Asp Thr Ile Gln Asn Gln Thr Thr Thr Met Leu Ala Leu Gly Ala Asn Leu Met Asn Gln Thr Lys Ala Gln Thr His Lys Leu Thr Ala Val Glu Ala Gln Val Leu Asn Gln Thr Leu His Met Lys Thr Gln Met Leu Glu Asn Ser Leu Ser Thr Asn Lys Leu Glu Arg Gin Met Leu Met Gln Ser Arg Glu Leu Gln Arg Leu Gln Gly Arg Asn Arg Ala Leu Glu Thr Arg Leu Gln Ala Leu Glu Ala Gln His Gin Ala Gln Leu Asn Ser Leu Gln Glu Lys Arg Glu Gln Leu His Ser Leu Leu Gly His Gln Thr Gly Thr Leu Ala Asn Leu Lys His Asn Leu His Ala Leu Ser Ser Asn Ser Ser Ser Leu Gln Gln Gln Gln Gln Gln Leu Thr Glu Phe Val Gln Arg Leu Val Arg Ile Val Ala Gin Asp Gin His Pro Val Ser Leu Lys Thr Pro Lys Pro Val Phe Gln Asp Cys Ala Glu Ile Lys Arg Ser Gly Val Asn Thr Ser Gly Val Tyr Thr Ile Tyr Glu Thr Asn Met Thr Lys Pro Leu Lys Val Phe Cys Asp Met Glu Thr Asp Gly Gly Gly Trp Thr Leu Ile Gln His Arg Glu Asp Gly Ser Val Asn Phe Gln Arg Thr Trp Glu Glu Tyr Lys Glu Gly Phe Gly Asn Val Ala Arg Glu His Trp Leu Gly Asn Glu Ala Val His A'rg Leu Thr Ser Arg Thr~Ala Tyr Leu Leu Arg Val Glu Leu His Asp Trp Glu Gly Arg Gln Thr Ser Ile Gln Tyr Glu Asn Phe Gln Leu Gly Ser Glu Arg Gln Arg Tyr Ser Leu Ser Val Asn Asp Ser Ser Ser Ser Ala Gly Arg Lys Asn Ser Leu Ala Pro Gln Gly Thr Lys Phe Ser Thr Lys Asp Met Asp Asn Asp Asn Cys Met Cys Lys Cys Ala Gln Met Leu Ser Gly Gly Trp Trp,Phe Asp Ala Cys Gly Leu Ser Asn Leu Asn Gly Ile Tyr Tyr Ser Val His Gln His Leu His Lys Ile Asn Gly Ile Arg Trp His Tyr Phe Arg Gly Pro Ser Tyr Ser , 485 490 495 Leu His Gly Thr Arg Met Met Leu Arg Pro Met Gly Ala (2) INFORMATION FOR SEQ ID N0:11:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 503 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (ix) FEATURE:

(A) NAME/KEY: mTL3 (B) LOCATION: 1...503 (D) OTHER INFORMATION: mouse TIE ligand-3 (xi) SEQUENCE DESCRIPTION: SEQ ID N0:11:

Met Leu Leu Asp Gly Leu Leu Leu Leu Ala Thr Met Ala Ala Ala Gln His Arg Gly Pro Glu Ala Gly Gly His Arg Gln Ile His Gln Val Arg Arg Gly Gln Cys Ser Tyr Thr Phe Val Val Pro Glu Pro Asp Ile Cys Gln Leu Ala Pro Thr Ala Ala Pro Glu Ala Leu Gly Gly Ser Asn Ser Leu Gln Arg Asp Leu Pro Ala Ser Arg Leu His Leu Thr Asp Trp Arg Ala Gln Arg Ala Gln Arg Ala Gln Arg Val Ser Gln Leu Glu Lys Ile Leu Glu Asn Asn Thr Gln Trp Leu Leu Lys Leu Glu Gln Ser Ile Lys Val Asn Leu Arg Ser His Leu Val Gln Ala Gln Gln Asp Thr Ile Gln Asn Gln Thr Thr Thr Met Leu Ala Leu Gly Ala Asn Leu Met Asn Gln Thr Lys Ala Gin Thr His Lys Leu Thr Ala Val Glu Ala Gln Val Leu Asn Gin Thr Leu His Met Lys Thr Gln Met Leu Glu Asn Ser Leu Ser Thr Asn Lys Leu Glu Arg Gln Met Leu Met Gln Ser Arg Glu Leu Gln Arg Leu Gln Gly Arg Asn Arg Ala Leu Glu Thr Arg Leu G1n Ala Leu ..~,, Glu Ala Gln His Gln Ala Gln Leu Asn Ser Leu Gln Glu Lys A rg Glu Gln Leu His Ser Leu Leu Gly His Gln Thr Gly Thr Leu Ala Asn Leu 225 2~0 235 240 Lys His Asn Leu His Ala Leu Ser Ser Asn Ser Ser Ser Leu G ln Gln Gln Gln Gln Gln Leu Thr Glu Phe Val Gln Arg Leu Val Arg Ile Val Ala Gln Asp G1n His Pro Val Ser Leu Lys Thr Pro Lys Pro Val Phe Gln Asp Cys Ala Glu Ile Lys Arg Ser Gly Val Asn Thr Ser Gly Val Tyr Thr Ile Tyr Glu Thr Asn Met Thr Lys Pro Leu Lys Val Phe Cys Asp Met Glu Thr Asp Gly Gly Gly Trp Thr Leu Ile Gln His Arg Glu 325 330 , = 3 33 Asp Gly Ser Val Asn Phe Gln Arg Thr Trp Glu Glu Tyr Lys Glu Gly Phe Gly Asn ValAla Arg Glu His Trp Leu Gly Asn Glu Ala Val His 355 360 365 ' Arg Leu Thr Ser Arg Thr Ala Tyr Leu Leu Arg Val Glu Leu His Asp Trp Glu Gly Arg Gin Thr Ser Ile Gln Tyr Glu Asn Phe Gln Leu Gly Ser Glu Arg Gin Arg Tyr Ser Leu Ser Val AsnAsp Ser Ser Ser Ser Ala Gly Arg Lys Asn Ser Leu Ala Pro Gln Giy Thr Lys Phe Ser Thr Lys Asp Met Asp Asn Asp Asn Cys Met Cys Lys Cys Ala G,ln Met Leu Ser Gly Gly Trp Trp Phe Asp Ala Cys Gly Leu Ser Asn Leu Asn Gly Ile Tyr Tyr Ser Val His Gln His Leu His Lys Ile Asn Gly Ile Arg Trp His Tyr Phe Arg Gly Pro Ser Tyr Ser Ile His Gly Thr Arg Met Met Leu Arg Pro Met Gly Ala (2) INFORMATION FOR SEQ ID NO:12:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 490 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (ix) FEATURE:

(A) NAME/KEY: hTLl (B) LOCATION: 1...490 (D) OTHER INFORMATION: human TIE-2 ligand 1 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12:

Ala Phe Leu Ala Ala Ile Leu Thr His Ile Gly Cys Ser Asn Gin Arg Arg Ser Pro Glu Asn Ser Gly Arg Arg Tyr Asn Arg Ile Gln His Gly Gin Cys Ala Tyr Thr Phe Ile Leu Pro Glu His Asp Gly Asn Cys Arg Glu Ser Thr Thr Asp Gln Tyr Asn Thr Asn Ala Leu Gln Arg Asp Ala Pro His Val Glu Pro Asp Phe Ser Ser Gln Lys Leu Gln His Leu Glu His Val Met Glu Asn Tyr Thr Gln Trp Leu Gin Lys Leu Glu Asn Tyr Ile Val Glu Asn Met Lys Ser Glu Met Ala G1n Ile Gln Gln Asn Ala 100 1 105 ', 110 Val Gin Asn His Thr Ala Thr Met Leu Glu Ile Gly Thr Ser Leu Leu Ser Gln Thr Ala Glu Gln Thr Arg Lys Leu Thr Asp Val Glu Thr Gln Val Leu Asn Gln Thr Ser Arg Leu Glu Ile Gln Leu Leu Glu Asn Ser Leu Ser Thr Tyr Lys Leu Glu Lys Gin Leu Leu G1nHG1n Thr Asn Glu Ile Leu Lys Ile His Glu Lys Asn Ser Leu Leu Glu His Lys Ile Leu Glu Met Glu Gly Lys His Lys Glu Glu Leu Asp Thr Leu Lys Glu Glu Lys Glu Asn Leu Gln G1y Leu Val Thr Arg Gln Thr Tyr Ile Ile Gln Glu Leu Glu Lys,Gln Leu Asn Arg Ala Thr Thr Asn Asn Ser Val Leu Gln Lys Gln Gln Leu Glu Leu Met Asp Thr Val His Asn Leu Val Asn Leu Cys Thr Lys Glu Val Leu Leu Lys Gly Gly Lys Arg Glu Glu Glu Lys Pro Phe Arg Asp Cys Ala Asp Val Tyr Gin Ala Gly Phe Asn Lys Ser Gly Ile Tyr Thr Ile Tyr Ile Asn Asn Met Pro Glu Pro Lys Lys Val Phe Cys Asn Met Asp Val Asn Gly Gly Gly Trp Thr Val Ile Gln His Arg Glu Asp Giy Ser Leu Asp Phe Gln Arg Gly Trp Lys Glu Tyr Lys Met Gly Phe Gly Asn Pro Ser Gly Glu Tyr Trp Leu Gly Asn Glu Phe Ile Phe Ala Ile Thr Ser Gln Arg Gln Tyr Met Leu Arg Ile Glu Leu Met Asp Trp Glu Gly Asn Arg Ala Tyr Ser Gln Tyr Asp Arg Phe His Ile Gly Asn Giu Lys Gln Asn Tyr Arg Leu Tyr Leu Lys Gly His Thr Gly Thr Ala Gly Lys Gln Ser Ser Leu Ile Leu His Gly Ala Asp Phe Ser Thr Lys Asp Ala Asp Asn Asp Asn Cys Met Cys Lys Cys Ala Leu Met Leu Thr Gly Gly Trp Trp Phe Asp Ala Cys Gly Pro Ser Asn Leu Asn Gly Met Phe Tyr Thr Ala Gly Gln Asn His Gly Lys Leu Asn Gly lie Lys Trp His Tyr Phe Lys Gly Pro Ser Tyr Ser Ile Arg Ser Thr Thr Met Met Ile Arg Pro Leu Asp Phe (2) INFORMATION FOR SEQ ID NO:13:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 491 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (ix) FEATURE:

(A) NAME/KEY: chTLl (B) LOCATION: 1...491 (D) OTHER INFORMATION: chicken TIE-2 ligand 1 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13:

Ala Phe Leu Ala Ala Ile Leu Ala His Ile Gly Cys Thr Thr Gln Arg Arg Ser Pro Glu Asn Ser Gly Arg Arg Phe Asn Arg Ile Gln His Gly Gln Cys Thr Tyr Thr Phe Ile Leu Pro Glu Gln Asp Gly Asn Cys Arg Glu Ser Thr Thr Asp Gln Tyr Asn Thr Asn Ala Leu Cln Arg Asp Ala Pro His Val Glu Gln Asp Phe Ser Phe Gin Lys Leu Gln His Leu Glu His Val Met Glu Asn Tyr Thr G1n Trp Leu Gln Lys Leu Glu Ser Tyr Ile Val Glu Asn Met Lys Ser Glu Met Ala Gln Leu Gln Gln Asn Ala Val Gln Asn HisThr Ala Thr Met Leu Glu Ile Gly Thr Ser Leu Leu Ser Gln Thr Ala Glu Gln Thr Arg Lys Leu Thr Asp Val Glu TMr Gln Val Leu Asn Gln Thr Ser Arg Leu Glu Ile Gln Leu Leu Glu Asn Ser Leu Ser Thr Tyr Lys Leu Glu Lys Gln Leu Leu,Gln Gln Thr Asn Glu Ile Leu Lys Ile His Glu Lys Asn Ser Leu Leu Glu His Lys Ile Leu Glu Met Glu Glu Arg His Lys Glu Glu Met Asp Thr Leu Lys Glu Glu Lys Glu Asn Leu Gln Gly Leu Val Thr Arg Gln Ser Tyr Ile Ile Gln Glu Leu Glu Lys Gln Leu Asn Lys Ala Thr Thr Asn Asn Ser Val Leu Gln Lys Gln Gln Leu Glu Leu Met Asp Thr Val His Thr Leu Ile Thr Leu Cys Ser Lys Glu Gly Val Leu Leu Lys Asn Ala Lys Arg Glu Glu Glu Lys Pro Phe Arg Asp Cys Ala Asp Val Tyr Gln Ala Gly Phe Asn Lys Ser Gly Ile Tyr Thr Ile Tyr Ile Asn Asn Val Ser Asp Pro Lys Lys Val Phe Cys Asn Met Asp Val Asn Gly Gly Gly Trp Thr Val Ile Gln His Arg Glu Asp Gly Ser Leu Asp Phe Gln Lys Gly Trp Lys Glu Tyr Lys Met Gly Phe Gly Ser Pro Ser Gly Glu Tyr Trp Leu Gly Asn Glu Phe Ile Phe Ala Ile Thr Ser Gln Arg Gin Tyr Ser Leu Arg Ile Glu Leu Met Asp Trp Glu Gly Asn Arg Ala Tyr Ser Gln Tyr Asp Arg Phe His Ile Gly Asn Glu Lys Gln Asn Tyr Arg Leu Tyr Leu Lys Gly His Ser Gly Thr Ala Gly Lys Gln Ser Ser Leu Ile Leu His Gly Ala Glu Phe Ser Thr Lys Asp Ala Asp Asn Asp Asn Cys Met Cys Lys Cys Ala Leu Met Leu Thr Gly Gly Trp Trp Phe Asp Ala Cys Gly Pro Ser Asn Leu Asn Gly Met Phe Tyr Thr Ala Gly Gln Asn His Gly Lys Leu Asn Gly Ile Lys Trp His Tyr Phe Lys Gly Pro Arg Tyr Ser Ile Arg Ser Thr Thr Met Met Ile Arg Pro Leu Asp Phe (2) INFORMATION FOR SEQ ID NO:14:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 497 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (ix) FEATURE:

(A) NAME/KEY: mTLl (B) LOCATION: 1...497 (D) OTHER INFORMATION: mouse TIE-2 ligand 1 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14:

Met Thr Val Phe Leu Ser Phe Ala Phe Phe Ala Ala Ile Leu Thr His Ile Gly Cys Ser Asn Gln Arg Arg Asn Pro Glu Asn Ser Gly Arg Arg Tyr Asn Arg Ile Gln His Gly Gln Cys Ala Tyr Thr Phe Ile Leu Pro Glu His Asp Gly Asn Cys Arg Glu Ser Thr Thr Asp Gln Tyr Asn Thr Asn Ala Leu Gln Arg Asp Ala Pro His Val Glu Pro Asp Phe Ser Ser Gln Lys Leu Gln His Leu Glu His Val Met Glu Asn Tyr Thr Gln Trp Leu Gln Lys Leu Glu Asn Tyr Ile Val Glu Asn Met Lys Ser Glu Met Ala Gln Ile Gln G1n Asn Ala Val Gln Asn His Thr Ala Thr Met Leu Glu Ile Gly Thr Ser Leu Leu Ser Gln Thr Ala Glu Gln Thr Arg Lys Leu Thr Asp Val Glu Thr Gln Val Leu Asn Gln Thr Ser Arg Leu Glu Ile Gln Leu Leu Glu Asn Ser Leu Ser Thr Tyr Lys Leu Glu Lys Gln Leu Leu Gin Thr Asn Glu Ile Leu Lys Ile His Glu Lys Asn Ser Leu Leu Glu His Lys Ile Leu Glu Met Glu Gly Lys His Lys Glu Glu Met Asp Thr Leu Lys Glu Glu Lys Glu Asn Leu Gln Gly Leu Val Ser Arg Gln Ser Phe Ile Ile Gln Glu Leu Glu Lys Gln Leu Ser Arg Ala Thr Asn Asn Asn Ser Ile Leu Gln Lys Gln Gln Leu Glu Leu Met Asp Thr Val His Asn Leu Ile Ser Leu Cys Thr Lys Glu Gly Val Leu Leu Lys Gly Gly Lys Arg Glu Glu Glu Lys Pro Phe Arg Asp Cys Ala Asp Val Tyr Gln Ala Gly Phe Asn Lys Ser Gly Ile Tyr Thr Ile Tyr Phe Asn Asn Val Pro Glu Pro Lys Lys Val Phe Cys Asn Met Asp Val Asn Gly Gly Gly Trp Thr Val Ile Gln His Arg Glu Asp Gly Ser Leu Asp Phe Gln Lys Gly Trp Lys Glu Tyr Lys Met Gly Phe Gly Ser Pro Ser Gly Glu Tyr Trp Leu Gly Asn Glu Phe Ile Phe Ala Ile Thr Ser Gln Arg Gln Tyr Met Leu Arg Ile Glu Leu Met Asp Trp Glu Gly Asn Arg Ala Tyr Ser Gln Tyr Asp Arg Phe His Ile Gly Asn Glu Lys Gln Asn Tyr Arg Leu Tyr Leu Lys Gly His Thr Gly Thr Ala Gly Lys Gln Ser Ser Leu Ile Leu His Gly Aia Asp Phe Ser Thr Lys Asp~Ala Asp Asn Asp Asn Cys Met Cys Lys Cys Ala Leu Met Leu Thr Gly Gly Trp Trp Phe Asp Ala Cys Gly Pro Ser Asn Leu Asn Gly Met Phe Tyr Thr Ala Gly Gln Asn His Gly Lys Leu Asn Gly Ile Lys Trp His Tyr Phe Lys Gly Pro Arg Tyr Ser Ile Arg Ser Thr Thr Met Met Ile Arg Pro Leu Asp Phe (2) INFORMATION FOR SEQ ID NO:15:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 496 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (ix) FEATURE:

(A) NAME/KEY: mTL2 (B) LOCATION: 1...496 (D) OTHER INFORMATION: mouse TIE-2 ligand 2 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:15:

Met Trp Gln Ile Ile Phe Leu Thr Phe Gly Trp Asp Ala Val Leu Thr Ser Ala Tyr Ser Asn Phe Arg Lys Ser Val Asp Ser Thr Gly Arg Arg Arg Tyr Arg Ile Gln Asn Gly Pro Cys Ala Tyr Thr Phe Leu Leu Pro Glu Thr Asp Ser Gly Arg Ser Ser Ser Ser Thr Tyr Met Thr Asn Ala Val Gln Arg Asp Ala Pro Pro Asp Tyr Glu Asp Ser Val Gln Ser Leu Gln Leu Leu Glu Asn Val Met Glu Asn Tyr Thr Gln Trp Leu Met Lys Leu Glu Asn Tyr Ile Gin Asp Asn Met Lys Lys Glu Met Ala Glu Ile Gln Gln Asn Val Val Gln Asn His Thr Ala Val Met Ile Glu Ile Gly Thr Ser Leu Leu Ser Gln Thr Ala Glu Gln Thr Arg Lys Leu Thr Asp Val Glu Thr Gln Val Leu Asn Gln Thr Thr Arg Leu Glu Leu Gin Leu Leu Gin His Ser Ile Ser Thr Tyr Lys Leu Glu Lys Gln Ile Leu Asp Gin Thr Ser Glu Ile Asn Lys Ile His Asn Lys Asn Ser Phe Leu Glu Gln Lys Val Leu Asp Met Glu Gly Lys His Ser Glu Glu Met Gln Thr Met Lys Glu Gln Lys Asp Glu Leu Gin Val Leu Val Ser Lys Gln Ser Ser Val Ile Asp Glu Leu Glu Lys Lys Leu Val Thr Ala Thr Val Asn Asn Ser Leu Leu Gln Lys Gln Gln His Asp Leu Met Asp Thr Val Asn Ser Leu Leu Thr Met Met Ser Ser Pro Asn Ser Lys Ser Ser Leu Ala Ile Arg Arg Glu Glu Gin Thr Thr Phe Arg Asp Cys Ala Asp Val Phe Lys Ala Gly Leu Thr Lys Ser Gly Ile Tyr Thr Leu !Thr Phe Pro Asn Ser Pro Glu Glu Ile Lys Ala Tyr Cys Asn Met Asp Val Gly Gly Gly Gly Trp Thr Val Ile Gln His Arg Glu Asp Gly Ser Leu Asp Phe Gln Lys Gly Trp Lys Glu Tyr Lys Met Gly Phe Gly Asn Pro Leu Gly Glu Tyr Trp Leu Gly Asn Glu Phe Ile Ser Gln Ile Thr Gly Gln His Arg Tyr Val Leu Lys Ile Gln Leu Lys Asp Trp Glu Gly Asn Glu Ala His Ser Leu Tyr Asp His Phe Tyr Ile Ala Gly Glu Glu Ser Asn Tyr Arg Ile His Leu Thr Gly Leu Thr Gly Thr Ala Ala Lys Ile Ser Ser Ile Ser Gln Pro Gly Ser Asp Phe Ser Thr Lys Asp Ser Asp Asn Asp Lys Cys Ile Cys Lys Cys Ser Leu Met Leu Thr Gly Gly Trp Trp Phe Asp Ala Cys Gly Pro Ser Asn Leu Asn Gly Gln Phe Tyr Pro Gln Lys Gln Asn Thr Asn Lys Phe Asn Gly Ile Lys Trp Tyr Tyr Trp Lys Gly Ser Gly Tyr Ser I1e Lys Ala Thr Thr Met Met Ile Arg Pro Ala Asp Phe (2) INFORMATION FOR SEQ ID NO:16:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 496 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (ix) FEATURE:

(A) NAME/KEY: hTL2 (B) LOCATION: 1...496 (D) OTHER INFORMATION: human TIE-2 ligand 2 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:16:

Met Trp Gln Ile Val Phe Phe Thr Leu Ser Cys Asp Ala Val Leu Thr Ala Ala Tyr Asn Asn Phe Arg Lys Ser Met Asp Ser Ile Gly Lys Lys Arg Tyr Arg Ile Gln His Gly Ser Cys Ala Tyr Thr Phe Leu Leu Pro Glu Met Asp Asn Gly Arg Ser Ser Ser Ser Thr Tyr Val Thr Asn Ala Val Gin Arg Asp Ala Pro Pro Glu Tyr Glu Asp Ser Val Gln Ser Leu Gln Leu Leu Glu Asn Val Met Glu Asn Tyr Thr Gin Trp Leu Met Lys Leu Glu Asn Tyr Ile Gln Asp Asn Met Lys Lys Glu Met Ala Glu Ile Gln Gln Asn Ala Val Gln Asn His Thr Ala Val Met Ile Glu Ile Gly Thr Ser Leu Leu Ser Gln Thr Ala Glu Gln Thr Arg Lys Leu Thr Asp Val Glu Thr Gln Val Leu Asn Gln Thr Thr Arg Leu Glu Leu Gln Leu Leu GIn His Ser Ile Ser Thr Tyr Lys Leu Glu Lys Gln Ile Leu Asp Gln Thr Ser Glu Ile Asn Lys Ile His Asp Lys Asn.,Ser Phe Leu Glu 180 , 185 190 Lys Lys Vai Leu Asp Met Glu Asp Lys His Ile Ile Glu Met Gin Thr Ile Lys Glu Glu Lys Asp Glu Leu Gln Val Leu Val Ser Lys Gin Asn Ser Ile Ile Glu Glu Leu Glu Lys Lys Ile Val Thr Ala Thr Val Asn Asn Ser Va1 Leu Gln Lys Gln Gln His Asp Leu Met Asp Thr Val Asn Asn Leu Leu Thr Met Met Ser Thr Ser Asn Ser Ala Lys Asp Ser Thr Val Ala Arg Glu G1u Gln Ile Ser Phe Arg Asp Cys Ala Asp Val Phe Lys Ala Gly His Thr Lys Asn Gly Ile Tyr Thr Leu Thr Phe Pro Asn Ser Pro Glu Glu Ile Lys Ala Tyr Cys Asn Met Asp Ala G1y Gly Gly Gly Trp Thr Ile Ile Gln Arg Arg Glu Asp Gly Ser Leu Asp Phe Gin Lys Gly Trp Lys Glu Tyr Lys Val Gly Phe Gly Ser Pro Ser Gly Glu 340 345 350 Tyr Trp Leu Gly Asn Glu Phe Ile Ser Gln Ile Thr Asn G1n Gln Arg Tyr Val Leu Lys Ile His Leu Lys Asp Trp Glu Gly Asn Glu Ala Tyr Ser Leu Tyr Asp His Phe Tyr Ile Ser Gly Glu Glu Leu Asn Tyr Arg Ile His Leu Lys Gly Leu Thr Gly Thr Ala Ala Lys Ile Ser Ser Ile Ser Gln Pro Gly Asn Asp Phe Ser Thr Lys Asp Gly Asp Asn Asp Lys -Cys Ile Cys Lys Cys Ser Leu Met Leu Thr Gly Gly Trp Trp Phe Asp Ala Cys Gly Pro Ser Asn Leu Asn Gly Met Phe Tyr Pro Gln Arg Gln Asn Thr Asn Lys Phe Asn Gly Ile Lys Trp Tyr Tyr Trp Lys Gly Ser Gly Tyr Ser Ile Lys Ala Thr Thr Met Met Ile Arg Pro Ala Asp Phe (2) INFORMATION FOR SEQ ID NO:17:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 1512 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA
(ix) FEATURE:

(A) NAME/KEY: Coding Sequence (B) LOCATION: 1...1509 (D) OTHER INFORMATION:

(A) NAME/KEY: TIE ligand-4 (B) LOCATION: 1...1512 (D) OTHER INFORMATION:

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:17:

ATG CTC TCC CAG CTA GCC ATG CTG CAG GGC AGC CTC CTC CTT GTG

Met Leu Ser Gln Leu Ala Met Leu Gln Gly Ser Leu Leu Leu Val Val GCC ACC ATG TCT GTG GCT CAA CAG ACA AGG CAG GAG GCG GAT

Ala Thr Met Ser Val Ala Gin Gln Thr Arg Gln Glu Ala Asp Arg Gly Cys Glu Thr Leu Val Val Gln His Gly His Cys Ser Tyr Thr Phe Leu CTG CCC AAG TCT GAG CCC TGC CCT CCG GGG CCT GAG GTC TCC AGG

Leu Pro Lys Ser Glu Pro Cys Pro Pro Gly Pro Glu Val Ser Arg Asp TCC AAC ACC CTC CAG AGA GAA TCA CTG GCC AAC CCA CTG CAC GTG

Ser Asn Thr Leu Gln Arg Glu Ser Leu Ala Asn Pro Leu His Leu Gly AAG TTG CCC ACC CAG CAG GTG AAA CAG CTG GAG CAG GCA CTG

Lys Leu Pro Thr Gln Gln Val Lys Gln Leu Glu Gln Ala Leu Gln Asn AAC ACG CAG TGG CTG AAG AAG CTA GAG AGG GCC ATC AAG ACG

Asn Thr Gln Trp Leu Lys Lys Leu Glu Arg Ala Ile Lys Thr Ile Leu AGG TCG AAG CTG GAG CAG GTC CAG CAG CAA ATG GCC CAG AAT

Arg Ser Lys Leu Glu Gln Val Gln Gln Gln Met Ala Gln Asn Gln Thr GCC CCC ATG CTA GAG CTG GGC ACC AGC CTC CTG AAC CAG ACC ACT

Ala Pro Met Leu Glu Leu Gly Thr Ser Leu Leu Asn Gln Thr Thr Ala CAG ATC CGC AAG CTG ACC GAC ATG GAG GCT CAG CTC CTG AAC

Gln Ile Arg Lys Leu Thr Asp Met Glu Ala Gin Leu Leu Asn Gln Thr TCA AGA ATG GAT GCC CAG ATG CCA GAG ACC TTT CTG TCC ACC AAC

Ser Arg Met Asp Ala Gln Met Pro Glu Thr Phe Leu Ser Thr Asn Lys CTG GAG AAC CAG CTG CTG CTA CAG AGG CAG AAG CTC CAG CAG

Leu Glu Asn Gln Leu Leu Leu Gln Arg Gln Lys Leu Gln G1n Leu Gln GGC CAA AAC AGC GCG CTC GAG AAG CGG TTG CAG GCC CTG GAG

Gly Gln Asn Ser Ala Leu Glu Lys Arg Leu Gln Ala Leu Glu Thr Lys CAG CAG GAG GAG CTG GCC AGC ATC CTC AGC AAG AAG GCG AAG

Gln Gln Glu Glu Leu Ala Ser Ile Leu Ser Lys Lys Ala Lys Leu Leu AAC ACG CTG AGC CGC CAG AGC GCC GCC CTC ACC AAC,ATC GAG

Asn Thr Leu Ser Arg Gln Ser Ala Ala Leu Thr Asn Ile Glu Arg Gly CTG CGC GGT GTC AGG CAC AAC TCC AGC CTC CTG CAG GAC CAG

Leu Arg Gly Val Arg His Asn Ser Ser Leu Leu Gin 481sp Gin G1n His AGC CTG CGC CAG CTG CTG GTG TTG TTG CGG CAC CTG GTG CAA GAA

Ser Leu Arg Gin Leu Leu Val Leu Leu Arg HiS Leu Vai Gin Glu Arg GCT AAC GCC TCG,GCC CCG GCC TTC ATA ATG GCA GGT GAG CAG GTG
TTC 864 ' Ala Asn Ala Ser Ala Pro Ala Phe Ile Met Ala Gly Glu Gln Val Phe CAG GAC TGT GCA GAG ATC CAG CGC TCT GGG GCC AGT GCC AGT

Gin Asp Cys Ala Glu Ile Gln Arg Ser Gly Ala Ser Ala Ser Gly Val TAC ACC ATC CAG GTG TCC AAT GCA ACG AAG CCC AGG AAG GTG

Tyr Thr Ile Gln Val Ser Asn Ala Thr Lys Pro Arg Lys Val Phe Cys GAC CTG CAG AGC AGT GGA GGC AGG TGG ACC CTC ATC CAG CGC

=Asp Leu Gln Ser Ser Giy Gly Arg Trp Thr Leu Ile Gln Arg Arg Glu AAT GGC ACC GTG AAT TTT CAG CGG AAC TGG AAG GAT TAC AAA

Asn Gly Thr Val Asn Phe Gln Arg Asn Trp Lys Asp Tyr Lys Gln Gly TTC GGA GAC CCA GCT GGG GAG CAC TGG CTG GGC AAT GAA GTG

Phe Gly Asp Pro Ala Gly Glu His Trp Leu Gly Asn Glu Val Val His CAG CTC ACC AGA AGG GCA GCC TAC TCT CTG CGT GTG GAG CTG CAA

Gln Leu Thr Arg Arg Ala Ala Tyr Ser Leu Arg Val Glu Leu Gln Asp TGG GAA GGC CAC GAG GCC TAT GCC CAG TAC GAA CAT TTC CAC CTG

Trp Glu Gly His Glu Ala Tyr Ala Gln Tyr Glu His Phe His Leu Gly AGT GAG AAC CAG CTA TAC AGG CTT TCT GTG GTC GGG TAC AGC GGC

Ser Glu Asn Gln Leu Tyr Arg Leu Ser Val Val Gly Tyr Ser Gly Ser GCA GGG CGC CAG AGC AGC CTG GTC CTG CAG AAC ACC AGC TTT

Ala Gly Arg Gin Ser Ser Leu Val Leu Glr, Asn Thr Ser Phe Ser Thr CTT GAC TCA GAC AAC GAC CAC TGT CTC TGC AAG TGT GCC CAG GTG

Leu Asp Ser Asp Asn Asp His Cys Leu Cys Lys Cys J1la Gin Val Met TCT GGA GGG TGG TGG TTT GAC GCC TGT GGC CTG TCA AAC CTC AAC

Ser Gly Gly Trp Trp Phe Asp Ala Cys Gly Leu Ser Asn Leu Asn Gly GTC TAC TAC CAC GCT CCC GAC AAC AAG TAC AAG ATG GAC GGC

Val Tyr Tyr His Ala Pro Asp Asn Lys Tyr Lys Met Asp Gly Ile Arg TGG CAC TAC TTC AAG GGC CCC AGC TAC TCA CTG CGT GCC TCT CGC

Trp His Tyr Phe,Lys Gly Pro Ser Tyr Ser Leu Arg Ala Ser Arg Met Met Ile Arg Pro Leu Asp Ile (2) INFORMATION FOR SEQ ID NO:18:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 503 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (v) FRAGMENT TYPE: internal (ix) FEATURE:

(A) NAME/KEY: TIE ligand-4 (B) LOCATION: 1...503 (D) OTHER INFORMATION:

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:18:

Met Leu Ser Gln Leu Ala Met Leu Gln Gly Ser Leu Leu Leu Val Val Ala Thr Met Ser Val Ala Gln Gln Thr Arg Gin Glu Ala Asp Arg Gly Cys Glu Thr Leu Val Val Gln His Gly His Cys Ser Tyr Thr Phe Leu Leu Pro Lys Ser Glu Pro Cys Pro Pro Gly Pro Glu Val Ser Arg Asp Ser Asn Thr Leu Gin Arg Glu Ser Leu Ala Asn Pro Leu His Leu Gly Lys Leu Pro Thr Gln Gln Val Lys Gin Leu Glu Gln Ala Leu Gln Asn Asn Thr Gln Trp Leu Lys Lys Leu Glu Arg Ala Ile Lys Thr Ile Leu Arg Ser Lys Leu Glu Gin Val Gln Gln Gln Met Ala Gln Asn Gln Thr Ala Pro Met Leu Glu Leu Gly Thr Ser Leu Leu Asn Gln Thr Thr Ala Gln Ile Arg Lys Leu Thr Asp Met Glu Ala Gln Leu Leu Asn Gln Thr Ser Arg Met Asp Ala Gin Met P r c Glu Thr Phe Leu Ser Thr Asn Lys Leu Glu Asn Gln Leu Leu Leu Gln Arg Gln Lys Leu Gln Gln Leu Gln Gly Gln Asn Ser Ala Lpu Glu Lys Arg Leu Gln Ala Leu Glu Thr Lys 195 200 ,205 Gln Gln Glu Glu Leu Ala Ser Ile Leu Ser Lys Lys Ala Lys Leu Leu Asn Thr Leu Ser Arg Gin Ser Ala Ala Leu Thr Asn Ile Glu Arg Gly Leu Arg Gly Val Arg His Asn Ser Ser Leu Leu Gln Asp Gln Gln His Ser Leu Arg Gln Leu Leu Val Leu Leu Arg His Leu Val Gln Glu Arg Ala Asn Ala Ser Ala Pro Ala Phe Ile Met Ala Gly Glu Gln Val Phe Gln Asp Cys Ala Glu Ile Gln Arg Ser Gly Ala Ser Ala Ser Gly Val Tyr Thr Ile Gin Val Ser Asn Ala Thr Lys Pro Arg Lys Val Phe Cys Asp Leu Gln Ser'Ser Gly Gly Arg Trp Thr Leu Ile Gln Arg, Arg Glu Asn Gly Thr Val Asn Phe Gin Arg Asn Trp Lys Asp Tyr Lys Gln Gly Phe Gly Asp Pro Ala Gly Glu His Trp Leu Gly Asn Glu Val Val His Gln Leu Thr Arg Arg Ala Ala Tyr Ser Leu Arg,Val Glu Leu Gln Asp Trp Glu Gly His Glu Ala Tyr Ala Gln Tyr Glu His Phe His Leu Gly Ser Glu Asn Gln Leu Tyr Arg Leu Ser Val Val Gly Tyr Ser Gly Ser Ala Gly Arg Gin Ser Ser Leu Val Leu Gln Asn Thr Ser Phe Ser Thr Leu Asp Ser Asp Asn Asp His Cys Leu Cys Lys Cys Ala Gln Val Met Ser Gly Gly Trp Trp Phe Asp Ala Cys Gly Leu Ser Asn Leu Asn Gly Vai Tyr Tyr His Ala Pro Asp Asn Lys Tyr Lys Met Asp Gly Ile Arg Trp His Tyr Phe Lys Gly Pro Ser Tyr Ser Leu Arg Ala Ser Arg Met Met Ile Arg Pro Leu Asp Ile (2) INFORMATION FOR SEQ ID NO:19:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 1497 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA
(ix) FEATURE:

(A) NAME/KEY: Coding Sequence (B) LOCATION: 1...1494 (D) OTHER INFORMATION:

(A) NAME/KEY: 1N1C2F (chimera 1) (B) LOCATION: 1...1497 (D) OTHER INFORMATION:
(A) NAME/KEY: Other (B) LOCATION: 1...60 (D) OTHER INFORMATION: Putative leader sequence is encoded by nucleotides 1-60 (xi) SEQUENCE DESCRTPTION: SEQ ID NO:19:

ATG ACA GTT TTC GTT TCC TTT GCT TTC CTC GCT GCC ATT CTG ACT

Met Thr Val Phe Leu Ser Phe Ala Phe Leu Ala Ala Ile Leu Thr His ATA GGG TGC AGC AAT CAG CGC CGA AGT CCA GAA AAC AGT GGG

Ile Gly Cys Ser Asn Gln Arg Arg Ser Pro Glu Asn Ser Gly Arg Arg TAT AAC CGG ATT CAA CAT GGG CAA TGT GCC TAC ACT TTC ATT CTT

Tyr Asn Arg Ile Gln His Gly Gln Cys Ala Tyr Thr Phe Ile Leu Pro GAA CAC GAT GGC AAC TGT CGT GAG AGT ACG ACA GAC CAG TAC

Glu His Asp Gly Asn Cys Arg Glu Ser Thr Thr Asp Gln Tyr Asn Thr AAC GCT CTG CAG AGA GAT GCT CCA CAC GTG GAA CCG GAT TTC TCT

Asn Ala Leu Gln Arg Asp Ala Pro His Val Glu Pro Asp Phe Ser Ser CAG AAA CTT CAA CAT CTG GAA CAT GTG ATG GAA AAT TAT ACT CAG

Gln Lys Leu Gin His Leu Glu His Val Met Glu Asn Tyr Thr Gln Trp CTG CAA AAA CTT GAG AAT TAC ATT GTG GAA AAC ATG AAG TCG

Leu Gln Lys Leu Glu Asn Tyr Ile Val Glu Asn Met Lys Ser Glu Met GCC CAG ATA CAG CAG AAT GCA GTT CAG AAC CAC ACG GCT ACC

Ala Gln Ile Gin Gln Asn Ala Val Gln Asn His Thr Ala Thr Met Leu GAG ATA GGA ACC AGC CTC CTC TCT CAG ACT GCA GAG CAG ACC

Glu Ile Gly Thr Ser Leu Leu Ser Gln Thr Ala Glu Gln Thr Arg Lys CTG ACA GAT GTT GAG ACC CAG GTA CTA AAT CAA ACT TCT CGA CTT

Leu Thr Asp Val Glu Thr Gln Val Leu Asn Gln Thr Ser Arg Leu Glu ATA CAG CTG CTG GAG AAT TCA TTA TCC ACC TAC AAG CTA GAG AAG

Ile Gln Leu Leu Glu Asn Ser Leu Ser Thr Tyr Lys Leu Glu Lys Gln CTT CTT CAA CAG ACA AAT GAA ATC TTG AAG ATC CAT GAA AAA AAC

Leu Leu Gln Gin Thr Asn Glu Ile Leu Lvs Ile His Giu Lys Asn Ser TTA TTA GAA CAT AAA: ATC TTA GAA ATG GAA GGA AA7~ CAC P.AG

Leu Leu Glu His Lys Ile Leu Glu Met Glu Gly Lys His Lys Glu Glu TTG GAC ACC TTA AAG GAA GAG AAA GAG AAC CTT CAA GGC TTG

Leu Asp Thr Leu Lys Glu Glu Lys Glu Asn Leu Gln Gly Leu Val Thr CGT CAA ACA TAT ATA ATC CAG GAG CTG GAA AAG CAA TTA AAC

Arg Gln Thr Tyr Ile Ile Gln Glu Leu Glu Lys Gin Leu Asn Arg Ala ACC ACC AAC AAC AGT GTC CTT CAG AAG CAG CAA CTG GAG CTG

Thr Thr Asn Asn Ser Val Leu Gln Lys Gln Gln Leu Glu Leu Met Asp ACA GTC CAC AAC CTT GTC AAT CTT TGC ACT AAA GAA GGT GTT TTA
CTA 816 ' Thr Val His Asn Leu Val Asn Leu Cys Thr Lys Glu Gly Val Leu Leu AAG GGA GGA AAA AGA GAG GAA GAG AAA CCA TTT AGA GAC TGT

Lys Gly Gly Lys Arg Glu Glu Glu Lys Pro PheArg Asp Cys Ala Glu GTA TTC AAA TCA GGA CAC ACC ACA AAT GGC ATC TAC ACG TTA ACA

Val Phe Lys Ser Gly His Thr Thr Asn Gly Ile Tyr Thr Leu Thr Phe CCT AAT TCT ACA GAA GAG ATC AAG GCC TAC TGT GAC ATG GAA GCT

Pro Asn Ser Thr Glu Glu Ile Lys Ala Tyr Cys Asp Met Glu Ala Gly '305 310 315 320 GGA GGC GGG TGG ACA ATT ATT CAG CGA CGT GAG GAT GGC AGC

Gly Gly Gly Trp Thr Ile Ile Gln Arg Arg Glu Asp Gly Ser Val Asp TTT CAG AGG ACT TGG AAA GAA TAT AAA GTG GGA TTT GGT AAC CCT

Phe Gln Arg Thr Trp Lys Glu Tyr Lys Val Gly Phe Gly Asn Pro Ser GGA GAA TAT TGG CTG GGA AAT GAG TTT GTT TCG CAA CTG ACT AAT

Gly Glu Tyr Trp Leu Gly Asn Glu Phe Val Ser Gln Leu Thr Asn Gln CAA CGC TAT GTG CTT AAA ATA CAC CTT AAA GAC TGG GAA GGG

Gln Arg Tyr Val Leu Lys Ile His Leu Lys Asp Trp Glu Gly Asn Glu GCT TAC TCA TTG TAT GAA CAT TTC TAT CTC TCA AGT GAA GAA CTC

Ala Tyr Ser Leu Tyr Glu His Phe Tyr Leu Ser Ser Glu Glu Leu Asn TAT AGG ATT CAC CTT AAA GGA CTT ACA GGG ACA GCC GGC AAA

Tyr Ara Ile His Leu Lys Gly Leu Thr C-ly Thr Ala Gly Lys Ile Ser A B~ AGC ATC AGC CAA CCA GGA AAT GAT TTT AGC ACA AAG GAT GGA

Ser Ile Ser Gln Pro Gly Asn Asp Phe Ser Thr Lys Asp Gly Asp Asn GAC AAA TGT ATT TGC AAA TGT TCA CAA ATG CTA ACA GGA GGC TGG

Asp Lys Cys Ile Cys Lys Cys Ser Gln Met Leu Thr Gly Gly Trp Trp Phe Asp Ala Cys Gly Pro Ser Asn Leu Asn Gly Met Tyr Tyr Pro Gln AGG CAG AAC ACA AAT AAG TTC AAC GGC ATT APiA TGG TAC TAC

Arg Gln Asn Thr Asn Lys Phe Asn Gly Ile Lys Trp Tyr Tyr Trp Lys GGC TCA GGC TAT TCG CTC AAG GCC ACA ACC ATG ATG ATC CGA GCA

Gly Ser Gly Tyr Ser Leu Lys Ala Thr Thr Met Met Ile Arg Pro Ala Asp Phe (2) INFORMATION FOR SEQ ID NO:20:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 498 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (v) FRAGMENT TYPE: internal (ix) FEATURE:

(A) NAME/KEY: 1N1C2F (chimera 1) (B) LOCATION: 1...498 (D) OTHER INFORMATION:

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:20:

Met Thr Val Phe Leu Ser Phe Ala Phe Leu Ala Ala Ile Leu Thr His Ile Gly Cys Ser Asn Gln Arg Arg Ser Pro Glu Asn Ser Gly Arg Arg Tyr Asn Arg Ile Gln His Gly Gln Cys Ala Tyr Thr Phe Ile Leu Pro Glu His Asp Gly Asn Cys Arg Glu Ser Thr Thr Asp Gln Tyr Asn Thr Asn Ala Leu Gln Arg Asp Ala Pro His Val Glu Pro Asp Phe Ser Ser Gln Lys Leu Gln His Leu Glu His Val Met Glu Asn Tyr Thr Gln Trp Leu Gln Lys Leu Glu Asn Tyr Ile Val Glu Asn Met Lys Ser Glu Met Ala Gln Ile Gln Gln Asn Ala Val Gin Asn His Thr Ala Thr Met Leu Glu Ile Gly Thr Ser Leu Leu Ser Gln Thr Ala Glu Gln Thr Arg Lys Leu Thr Asp Val Glu Thr Gin Val Leu Asn Gln Thr Ser Arg Leu Glu Ile Gln Leu Leu Glu Asn Ser Leu Ser Thr Tyr Lys Leu Glu Lys Gln 165 ' 170 175 Leu Leu Gln Gln Thr Asn Glu Ile Leu Lys Ile His Glu Lys Asn Ser Leu Leu Glu His Lys Ile Leu Glu Met Glu Gly Lys His Lys Glu Glu Leu Asp Thr Leu Lys Glu Glu Lys Glu Asn Leu Gln Gly Leu Val Thr Arg Gln Thr Tyr Ile Ile Gln Glu Leu Glu Lys Gin Leu Asn Arg Ala Thr Thr Asn Asn Ser Val Leu Gln Lys Gln Gin Leu Glu Leu Met Asp Thr Val His Asn Leu Val Asn Leu Cys Thr Lys Glu Gly Val Leu Leu Lys Gly Gly Lys Arg Glu Giu Glu Lys Pro Phe Arg Asp Cys Ala Glu Val Phe Lys Ser,Gly His Thr Thr Asn Gly Ile Tyr Thr Leu Thr Phe Pro Asn Ser Thr Glu Glu Ile Lys Ala Tyr Cys Asp Met Glu Ala Gly Giy Gly Gly Trp Thr Ile Ile Gln Arg Arg Glu Asp Gly Ser Val Asp Phe Gln Arg Thr Trp Lys Glu Tyr Lys Val Gly Phe Gly Asn Pro Ser Gly Glu Tyr Trp Leu Gly Asn Glu Phe Val Ser Gln Leu Thr Asn Gln Gln Arg Tyr Val Leu Lys Ile His Leu Lys Asp Trp Glu Gly Asn Glu Ala Tyr Ser Leu Tyr Glu His Phe Tyr Leu Ser Ser Glu Glu Leu Asn Tyr Arg Ile His Leu Lys Gly Leu Thr Gly Thr Ala Gly Lys Ile Ser Ser Ile Ser Gln Pro Gly Asn Asp Phe Ser Thr Lys Asp Gly Asp Asn Asp Lys Cys Ile Cys Lys Cys Ser Gln Met Leu Thr Gly Gly Trp Trp Phe Asp Ala Cys Gly Pro Ser Asn Leu Asn Gly Met Tyr Tyr Pro Gln Arg Gln Asn Thr Asn Lys Phe Asn Gly Ile Lys Trp Tyr Tyr Trp Lys Gly Ser Gly Tyr Ser Leu Lys Ala Thr Thr Met Met Ile Arg Pro Ala Asp Phe (2) INFORMATION FOR SEQ ID NO:21:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 1491 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA
(ix) FEATURE:

(A) NAME/KEY: Coding Sequence (B) LOCATION: 1...1488 (D) OTHER INFORMATION:

(A) NAME/KEY: 2N2C1F (chimera 2) (B) LOCATION: 1...1491 (D) OTHER INFORMATION:

(A) NAME/KEY: Other (B) LOCATION: 1...48 (D) OTHER INFORMATION: Putative leader',sequence is encoded by nucleotides 1-48 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:21:

ATG TGG CAG ATT GTT TTC TTT ACT CTG AGC TGT GAT CTT GTC TTG

Met Trp Gln Ile Val Phe Phe Thr Leu Ser Cys Asp Leu Val Leu Ala GCA GCC TAT AAC AAC TTT CGG AAG AGC ATG GAC AGC ATA GGA

Ala Ala Tyr Asn Asn Phe Arg Lys Ser Met Asp Ser Ile Gly Lys Lys CAA TAT CAG GTC,CAG CAT GGG TCC TGC AGC TAC ACT TTC CTC CTG

Gln Tyr Gin Val Gin His Gly Ser Cys Ser Tyr Thr Phe Leu Leu Pro GAG ATG GAC AAC TGC CGC TCT TCC TCC AGC CCC TAC GTG TCC AAT

Glu Met Asp Asn Cys Arg Ser Ser Ser Ser Pro Tyr Val Ser Asn Ala GTG CAG AGG GAC GCG CCG CTC GAA TAC GAT GAC TCG GTG CAG

Val Gln Arg Asp Ala Pro Leu Glu Tyr Asp Asp Ser Val Gln Arg Leu CAA GTG CTG GAG AAC ATC ATG GAA AAC AAC ACT CAG TGG CTA

Gln Val Leu Glu Asn Ile Met Giu Asn Asn Thr Gln Trp Leu Met Lys CTT GAG AAT TAT ATC CAG GAC AAC ATG AAG AAA GAA ATG GTA

Leu Glu Asn Tyr Ile Gin Asp Asn Met Lys Lys Glu Met Val Glu Ile CAG CAG AAT GCA GTA CAG AAC CAG ACG GCT GTG ATG ATA GAA

Gln Gln Asn Ala Val Gln Asn Gln Thr Ala Val Met Ile Glu Ile Gly ACA AAC CTG TTG AAC CAA ACA GCT GAG CAA ACG CGG AAG TTA

Thr Asn Leu Leu Asn Gin Thr Ala Glu Gln Thr Arg Lys Leu Thr Asp GTG GAA GCC CAA GTA TTA AAT CAG ACC ACG AGA CTT GAA CTT

Val Glu Ala Gln Val Leu Asn Gln Thr Thr Arg Leu Glu Leu Gln Leu TTG GAA CAC TCC CTC TCG ACA AAC AAA TTG GAA AAA CAG ATT TTG

Leu Glu His Ser Leu Ser Thr Asn Lys Leu Glu Lys Gln Ile Leu Asp CAG ACC AGT GAA ATA AAC AAA TTG CAA GAT AAG AAC AGT TTC

Gin Thr Ser Glu Ile Asn Lys Leu Gin Asp Lys Asn Ser Phe Leu Glu AAG AAG GTG CTA GCT ATG GAA GAC AAG CAC ATC ATC CAA CTA
CAG TCA 624 , ' ' Lys Lys Val Leu Ala Met Glu Asp Lys His Ile Ile',Gln Leu Gin Ser ATA AAA GAA GAG AAA GAT CAG CTA CAG GTG TTA GTA TCC AAG

Ile Lys Glu G1u Lys Asp Gln Leu Gln Val Leu Val Ser Lys Gln Asn TCC ATC ATT GAA GAA CTA GAA AAA AAA ATA GTG ACT GCC ACG

Ser Ile Ile Glu Glu Leu Glu Lys Lys Ile Val Thr Ala Thr Val Asn AAT TCA GTT CTT CAA AAG CAG CAA CAT GAT CTC ATG GAG ACA GTT

Asn Ser Val Leu'Gln Lys Gln Gln His Asp Leu Met Glu Thr Val Asn AAC TTA CTG ACT ATG ATG TCC ACA TCA AAC TCA GCT AAG GAC CCC

Asn Leu Leu Thr Met Met Ser Thr Ser Asn Ser Ala Lys Asp Pro Thr GTT GCT AAA GAA GAA CAA ATC AGC TTC AGA GAC TGT GCA GAT

Val Ala Lys Glu Glu Gin Ile Ser Phe Arg Asp Cys Ala Asp Val Tyr CAA GCT GGT TTT AAT AAA AGT GGA ATC TAC ACT ATT TAT ATT AAT

Gln Ala Gly Phe Asn Lys Ser Gly Ile Tyr Thr Ile Tyr I1e Asn Asn ATG CCA GAA CCC AAA AAG GTG TTT TGC AAT ATG GAT GTC AAT GGG

Met Pro Glu Pro Lys Lys Val Phe Cys Asn Met Asp Val Asn Gly Gly GGT TGG ACT GTA ATA CAA CAT CGT GAA GAT GGA AGT CTA GAT TTC

Gly Trp Thr Val Ile Gln His Arg Glu Asp Gly Ser Leu Asp Phe Gln AGA GGC TGG AAG GAA TAT AAA ATG GGT TTT GGA AAT CCC TCC

Arg Gly Trp Lys Glu Tyr Lys Met Gly Phe Gly Asn Pro Ser Gly Glu TAT TGG CTG GGG AAT GAG TTT ATT TTT GCC ATT ACC AGT CAG AGG

Tyr Trp Leu Gly Asn Glu Phe Ile Phe Ala Ile Thr Ser Gln Arg Gln TAC ATG CTA AGA ATT GAG TTA ATG GAC TGG GAA GGG AAC CGA

Tyr Met Leu Arg Ile Glu Leu Met Asp Trp Glu Gly Asn Arg Ala Tyr TCA CAG TAT GAC AGA TTC CAC ATA GGA AAT GAA AAG CA.A AAC

Ser Gln Tyr Asp Arg Phe His Ile Gly Asn Glu Lys Gln Asn Tyr Arg X

TTG TAT TTA AAA GGT CAC ACT GGG ACA GCA GGA AAA CAG AGC

Leu Tyr Leu Lys Gly His Thr Gly Thr Ala Gly Lys Gln Ser Ser Leu ATC TTA CAC GGT GCT GAT TTC AGC ACT AAA GAT GCT GAT AAT GAC

Ile Leu His Gly Ala Asp Phe Ser Thr Lys Asp Ala Asp Asn Asp Asn TGT ATG TGC AAA TGT GCC CTC ATG TTA ACA GGA GGA TGG TGG TTT

Cys Met Cys Lys Cys Ala Leu Met Leu Thr Gly Gly Trp Trp Phe Asp GCT TGT GGC CCC TCC AAT CTA AAT GGA ATG TTC TAT ACT GCG GGA

Ala Cys Gly Pro Ser Asn Leu Asn Gly Met Phe Tyr Thr Ala Gly Gln AAC CAT GGA AAA CTG AAT GGG ATA AAG TGG CAC TAC TTC AAA

Asn His Gly Lys Leu Asn Gly Ile Lys Trp His Tyr Phe Lys Gly Pro AGT TAC TCC TTA CGT TCC ACA ACT ATG ATG ATT CGA CCT TTA GAT

Ser Tyr Ser Leu Arg Ser Thr Thr Met Met Ile Arg Pro Leu Asp Phe (2) INFORMATION FOR SEQ ID NO:22:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 496 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (v) FRAGMENT TYPE: internal (ix) FEATURE:

(A) NAME/KEY: 2N2C1F (chimera 2) (B) LOCATION: 1...496 (D) OTHER INFORMATION:

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:22:

Met Trp Gln Ile Val Phe Phe Thr Leu Ser Cys Asp Leu Val Leu Ala Ala Ala Tyr Asn Asn Phe Arg Lys Ser Met Asp Ser Ile Gly Lys Lys Gln Tyr Gln Val Gln His Gly Ser Cys Ser Tyr Thr Phe Leu Leu Pro Glu Met Asp Asn Cys Arg Ser Ser Ser Ser Pro Tyr Val Ser Asn Ala Val Gln Arg Asp Ala Pro Leu Glu Tyr Asp Asp Ser Val Gln Arg Leu Gln Val Leu Glu Asn Ile Met Glu Asn Asn Thr Gin Trp Leu Met Lys Leu Glu Asn Tyr Ile Gln Asp Asn Met Lys Lys Glu Met Val Glu Ile Gln Gln Asn Ala Val Gin Asn Gln Thr Ala Val Met Ile Glu Ile Gly 115 120 i25 n, q.u Thr Asn Leu Leu Asn Gln Thr Ala Glu Gln Thr Arg Lys Leu Thr Asp Val Glu Ala Gin Vai Leu Asn Gin Thr Thr Arg Leu Glu Leu Gln Leu Leu Glu His Ser Leu Ser Thr Asn Lys Leu Glu Lys 1Fln Ile Leu Asp Gln Thr Ser Glu Ile Asn Lys Leu Gln Asp Lys Asn Ser Phe Leu Glu Lys Lys Val Leu Ala Met Glu Asp Lys His Ile Ile Gln Leu Gln Ser Ile Lys Glu Glu Lys Asp Gln Leu Gln Val Leu Val Ser Lys Gln Asn 210 215 220 w Ser Ile Ile Glu Glu Leu Glu Lys Lys Ile Val Thr Ala Thr Val Asn Asn Ser Val Leu Gin Lys Gln G1n His Asp Leu Met Glu Thr Val Asn Asn Leu Leu Thr Met Met Ser Thr Ser Asn Ser, Ala Lys Asp Pro Thr Val Ala Lys Glu Glu Gln Ile Ser Phe Arg Asp Cys Ala Asp Val Tyr Gin Ala Gly Phe Asn Lys Ser Gly Ile Tyr Thr Ile Tyr Ile Asn Asn Met Pro Glu Pro Lys Lys Val Phe Cys Asn Met Asp Val Asn Gly Gly Gly Trp Thr Val Ile Gln His Arg Glu Asp Gly Ser Leu Asp Phe Gln Arg Gly Trp Lys Glu Tyr Lys Met Gly Phe Gly Asn Pro Ser Gly Glu Tyr Trp Leu Gly Asn Glu Phe Ile Phe Ala Ile Thr Ser Gln Arg Gln Tyr Met Leu Arg Ile Glu Leu Met Asp Trp Glu Gly Asn Arg Ala Tyr Ser Gln Tyr Asp Arg Phe His Ile Gly Asn Glu Lys Gln Asn Tyr Arg Leu Tyr Leu Lys Gly His Thr Gly Thr Ala Gly Lys Gln Ser Ser Leu Ile Leu His Gly Ala Asp Phe Ser Thr Lys Asp Ala Asp Asn Asp Asn Cys Met Cys Lys Cys Ala Leu Met Leu Thr Gly Gly Trp Trp Phe Asp Ala Cys Gly Pro Ser Asn Leu Asn Gly Met Phe Tyr Thr Ala Gly Gln Asn His Gly Lys Leu Asn Gly Ile Lys Trp His Tyr Phe Lys Gly Pro Ser Tyr Ser Leu Arg Ser Thr Thr Met Met Ile Arg Pro Leu Asp Phe (2) INFORMATION FOR SEQ ID NO:23:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH': 1500 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA
(ix) FEATURE:

(A) NAME/KEY: Coding Sequence (B) LOCATION: 1...1497 (D) OTHER INFORMATION:

(A) NAME/KEY: 1N2C2F (chimera 3) (B) LOCATION: 1...1500 (D) OTHER iNFORMATlON:

(A) NAME/KEY: Other (B) LOCATION: 1...60 (D) OTHER INFORMATION: Putative leader sequence is encoded by nucleotid6s 1-60 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:23:

Met Thr Val Phe Leu Ser Phe Ala Phe Leu Ala Ala Ile Leu Thr His Ile Gly Cys Ser Asn Gln Arg Arg Ser Pro Glu Asn Ser Gly Arg Arg Tyr Asn Arg Ile Gln His Gly Gln Cys Ala Tyr Thr Phe Ile Leu Pro Glu His Asp Gly Asn Cys Arg Glu Ser Thr Thr Asp Gin Tyr Asn Thr Asn Ala Leu Gln Arg Asp Ala Pro His Val Glu Pro Asp Asp Ser Val Gln Arg Leu Gln Val Leu Glu Asn Ile Met Glu Asn Asn Thr Gln Trp Leu Met Lys Leu Glu Asn Tyr Ile Gln Asp Asn Met Lys Lys Glu Met Val Glu Ile Gln Gln Asn Ala Val Gln Asn Gln Thr Ala Val Met Ile Glu Ile Gly Thr Asn Leu Leu Asn Gln Thr Ala Glu Gln Thr Arg Lys Leu Thr Asp Val Glu Ala Gln Val Leu Asn Gln Thr Thr Arg Leu Glu Leu Gln Leu Leu Glu His Ser Leu Ser Thr Asn Lys Leu Glu Lys Gln Ile Leu Asp Gln Thr Ser Glu Ile Asn Lys Leu Gln Asp Lys Asn Ser TTC CTA GAA AAG AAG GTG CTA GCT ATG GAA GAC AAG CAC ATC

Phe Leu Glu Lys Lys Val Leu Ala Met Glu Asp Lys His Ile Ile Gln 195 ' ' 200 ~205 CTA CAG TCA ATA AAA GAA GAG AAA GAT CAG CTA CAG GTG TTA

Leu Gin Ser Ile Lys Glu Glu Lys Asp Gln Leu Gln Val Leu Val Ser AAG CAA AAT TCC ATC ATT GAA GAA CTA GAA AAA AAA FpTA GTG

Lys Gln Asn Ser Ile Ile Glu Glu Leu Glu Lys Lys Ile Val Thr Ala ACG GTG AAT AAT TCA GTT CTT CAA AAG CAG CAA CAT GAT CTC ATG

Thr Val Asn Asn Ser Val Leu Gln Lys Gln Gln His Asp Leu Met Glu ACA GTT AAT AAC TTA CTG ACT ATG ATG TCC ACA TCA AAC TCA GCT

Thr Val Asn Asn Leu Leu Thr Met Met Ser Thr Ser Asn Ser Ala Lys GAC CCC ACT GTT GCT AAA GAA GAA CAA ATC AGC TTC AGA GAC

Asp Pro Thr Val Ala Lys Glu Glu Gln Ile Ser Phe Arg Asp Cys Ala 275 280 285 , GAA GTA TTC AAA TCA GGA CAC ACC ACA AAT GGC ATC TAC ACG

Glu Val Phe Lys Ser Gly His Thr Thr Asn Gly Ile Tyr Thr Leu Thr TTC CCT AAT TCT ACA GAA GAG ATC AAG GCC TAC TGT GAC ATG GAA

Phe Pro Asn Ser Thr Glu Glu Ile Lys Ala Tyr Cys Asp Met Glu Ala GGA GGA GGC GGG TGG ACA ATT ATT CAG CGA CGT GAG GAT GGC

Gly Gly Gly Gly Trp Thr Ile Ile Gln Arg Arg Glu Asp Gly Ser Val GAT TTT CAG AGG ACT TGG AAA GAA TAT AAA GTG GGA TTT GGT AAC

Asp Phe Gln Arg Thr Trp Lys Glu Tyr Lys Val Gly Phe Gly Asn Pro TCA GGA GAA TAT TGG CTG GGA AAT GAG TTT GTT TCG CAA CTG ACT

Ser Gly Glu Tyr Trp Leu Gly Asn Glu Phe Val Ser Gln Leu Thr Asn CAG CAA CGC TAT GTG CTT AAA ATA CAC CTT AAA GAC TGG GAA

Gln Gin Arg Tyr Val Leu Lys Ile His Leu Lys Asp Trp Glu Gly Asn GAG GCT TAC TCA TTG TAT GAA CAT TTC TAT CTC TCA AGT GAA GAA

Glu Ala Tyr Ser Leu Tyr Glu His Phe Tyr Leu Ser Ser Glu Glu Leu AAT TAT AGG ATT CAC CTT AkA GGF CTT ACA GGG ACA G C C GGC

Asn Tyr Arg Ile His Leu Lys Gly Leu Thr Gly Thr Ala Gly Lys Ile AGC AGC ATC AGC CAA CCA GGA AAT GAT TTT AGC ACA AAG GAT

Ser Ser Ile Ser Gln Pro Gly Asn Asp Phe Ser Thr Lys Asp Gly Asp AAC GAC AAA TGT ATT TGC AAA TGT TCA CAA ATG CTA ACA GGA

Asn Asp Lys Cys Ile Cys Lys Cys Ser Gin Met Leu Thr Gly Gly Trp TGG TTT GAT GCA TGT GGT CCT TCC AAC TTG AAC GGA ATG TAC TAT

Trp Phe Asp Ala Cys Gly Pro Ser Asn Leu Asn Gly Met Tyr Tyr Pro CAG AGG CAG AAC ACA AAT AAG TTC AAC GGC ATT AAA TGG TAC

Gln Arg Gln Asn Thr Asn Lys Phe Asn Gly Ile Lys Trp Tyr Tyr Trp AAA GGC TCA GGC TAT TCG CTC AAG GCC ACA ACC ATG ATG ATC

Lys Gly Ser Gly Tyr Ser Leu Lys Ala Thr Thr Met Met Ile Arg Pro Ala Asp Phe (2) INFORMATION FOR SEQ ID NO:24:
(i) SEQUENCE CHARACTERISTICS;
(A) LENGTH: 499 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (v) FRAGMENT TYPE: internal (ix) FEATURE:

(A) NAME/KEY: 1N2C2F (chimera 3) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:24:

Met Thr Val Phe Leu Ser Phe Ala Phe Leu Ala Ala Ile Leu Thr His Ile Gly Cys Ser Asn Gln Arg Arg Ser Pro Glu Asn Ser Gly Arg Arg Tyr Asn Arg Ile Gln His Gly Gln Cys Ala Tyr Thr Phe Ile Leu Pro Glu His Asp Gly Asn Cys Arg Glu Ser Thr Thr Asp Gln Tyr Asn Thr Asn Aia Leu Gin Arg Asp Ala Pro His Vai Glu Pro Asp Asp Ser Val Gln Arg Leu Gln Vai Leu Glu Asn Ile Met Glu Asn Asn Thr Gln Trp Leu Met Lys Leu Glu Asn Tyr Ile Gln Asp Asn Met Lys Lys Glu Met Val Glu Ile Gln Gln Asn Ala Val Gln Asn Gln Thr Ala Val Met Ile Giu Ile Gly Thr Asn 7-eu Leu Asn Gln Thr Ala Glu Gln Thr Arg Lys Leu Thr Asp Val Glu Ala Gln Val Leu Asn Gln Thr Thr Arg Leu Glu Leu Gln Leu Leu Glu His Ser Leu Ser Thr Asn Lys Leu Glu Lys Gln Ile Leu Asp Gln Thr Ser Glu Ile Asn Lys Leu Gln Asp Lys Asn Ser Phe Leu Glu Lys Lys Val Leu Ala Met Glu Asp Lys His Ile Ile Gln Leu Gln Ser Ile Lys Glu Glu Lys Asp G1n Leu Gln Val Leu Val Ser Lys Gln Asn Ser Ile Ile Glu Glu Leu Glu Lys Lys Ile Val Thr Ala Thr Val Asn Asn Ser Val Leu Gln Lys Gln Gin His Asp Leu Met Giu Thr Val Asn Asn Leu Leu Thr Met Met Ser Thr Ser Asn Ser Ala Lys Asp Pro Thr Val Ala Lys Glu Glu Gln Ile Ser Phe Arg Asp Cys Ala Glu Val Phe Lys 8er Gly His Thr Thr Asn Gly Ile Tyr Thr,Leu Thr Phe Pro Asn Ser Thr Glu Glu Ile Lys Ala Tyr Cys Asp Met Glu Ala Gly Giy Gly Gly Trp Thr Ile Ile Gln Arg Arg Glu Asp Gly Ser Val Asp Phe Gln Arg Thr Trp Lys Glu Tyr Lys Val Gly Phe Gly Asn Pro Ser Gly Glu Tyr Trp Leu Gly Asn Glu Phe Val Ser Gln Leu Thr Asn Gln Gln Arg Tyr Val Leu Lys IIe His Leu Lys Asp Trp Glu Gly Asn Glu Ala Tyr Ser Leu Tyr Glu His Phe Tyr Leu Ser Ser Glu Glu Leu Asn Tyr Arg Ile His Leu Lys Gly Leu Thr Gly Thr Ala Gly Lys Ile Ser Ser Ile Ser Gin Pro Gly Asn Asp Phe Ser Thr Lys Asp Gly Asp Asn Asp Lys Cys Ile Cys Lys Cys Ser Gln Met Leu Thr Gly Gly Trp Trp Phe Asp Ala Cys Gly Pro Ser Asn Leu Asn Gly Met Tyr Tyr Pro Gln Arg Gln Asn Thr Asn Lys Phe Asn Gly Ile Lys Trp Tyr Tyr Trp Lys Gly Ser Gly Tyr Ser Leu Lys Ala Thr Thr Met Met Ile Arg Pro Ala Asp Phe (2) INFORMATION FOR SEQ ID NO:25:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 1488 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA
(ix) FEATURE:

(A) NAME/KEY: Coding Sequence (B) LOCATION: 1...1485 (D) OTHER INFORMATION:

(A) NAME/KEY: 2N1C1F (chimera 4) (B) LOCATION: I ...1488 ,,,4.,=

(D) OTHER INFORMATION:
(A) NAME/KEY: Other (B) LOCATION': 1. .'. 48 (D) OTHER INFORMATION: Putative leader sequence (xi) SEQUENCE DESCRIPTION: SEQ ID NO:25:

ATG TGG CAG ATT GTT TTC TTT ACT CTG AGC TGT GAT CTT GTC TTG
GCC 48 y Met Trp Gin Ile Val Phe Phe Thr Leu Ser Cys Asp Leu Val Leu Ala GCA GCC TAT AAC AAC TTT CGG AAG AGC ATG GAC AGC ATA GGA

Ala Ala Tyr Asn Asn Phe Arg Lys Ser Met Asp Ser Ile Gly Lys Lys CAA TAT CAG GTC CAG CAT GGG TCC TGC AGC TAC ACT TTC CTt CTG
CCA 144 ' Gln Tyr Gln Val Gln His Gly Ser Cys Ser Tyr Thr Phe Leu Leu Pro GAG ATG GAC AAC TGC CGC TCT TCC TCC AGC CCC T,AC GTG TCC AAT

Glu Met Asp Asn Cys Arg Ser Ser Ser Ser Pro Tyr Val Ser Asn Ala GTG CAG AGG GAC GCG CCG CTC GAA TAC GAT TTC TCT TCC CAG AAA

Val Gln Arg Asp Ala Pro Leu Glu Tyr Asp Phe Ser Ser Gln Lys Leu CAA CAT CTG GAA CAT GTG ATG GAA AAT TAT ACT CAG TGG CTG CAA

Gin His Leu Glu His Val Met Glu Asn Tyr Thr Gln Trp Leu Gln Lys CTT GAG AAT TAC ATT GTG GAA AAC ATG AAG TCG GAG ATG GCC

Leu Glu Asn Tyr Ile Val Glu Asn Met Lys Ser Glu Met Ala Gln Ile CAG CAG AAT GCA GTT CAG AAC CAC ACG GCT ACC ATG CTG GAG

Gln Gln Asn Ala Val Gln Asn His Thr Ala Thr Met Leu Glu Ile Gly ACC AGC CTC CTC TCT CAG ACT GCA GAG CAG ACC AGA AAG CTG

Thr Ser Leu Leu Ser Gln Thr Ala Glu Gln Thr Arg Lys Leu Thr Asp GTT GAG ACC CAG GTA CTA AAT CAA ACT TCT CGA CTT GAG ATA CAG

Val Glu Thr Gln Val Leu Asn Gln Thr Ser Arg Leu Glu Ile Gln Leu CTG GAG AAT TCA TTA TCC ACC TAC AAG CTA GAG AAG CAF. CTT CTT

Leu Glu Asn Ser Leu Ser Thr Tyr Lys Leu Glu Lys Gln Leu Leu Gln CAG ACA AAT GAA ATC TTG AP.G ATC CAT GF,A AAF F.F C AG~_' TTA
TTA GP.A 576 Gln Thr Asn Glu Ile Leu Lys Ile His Glu Lys Asn Ser Leu Leu Glu CAT AAA ATC TTA GAA ATG GAA GGA AAA CAC AAG GAA GAG TTG

His Lys Ile Leu Glu Met Glu Gly Lys His Lys Glu Glu Leu Asp Thr TTA AAG GAA GAG AAA GAG AAC CTT CAA GGC TTG GTT ACT CGT

Leu Lys Glu Glu Lys Glu Asn Leu Gln Gly Leu Val Thr Arg Gln Thr TAT ATA ATC CAG GAG CTG GAA AAG CAA TTA AAC AGA GCT ACC

Tyr Ile Ile Gin Glu Leu Glu Lys Gln Leu Asn Arg Ala Thr Thr Asn AAC AGT GTC CTT CAG AAG CAG CAA CTG GAG CTG ATG GAC ACA

Asn Ser Val Leu Gln Lys Gln Gln Leu Glu Leu Met Asp Thr Val His AAC CTT GTC AAT CTT TGC ACT AAA GAA GGT GTT TTA CTA AAG GGA

Asn Leu Val Asn Leu Cys Thr Lys Glu Gly Val Leu Leu Lys Gly Gly AAA AGA GAG GAA GAG AAA CCA TTT AGA GAC TGT GCA GAT GTA

Lys Arg Glu Glu Glu Lys Pro Phe Arg Asp Cys Ala Asp Val Tyr Gln GCT GGT TTT AAT AAA AGT GGA ATC TAC ACT ATT TAT ATT AAT AAT

Ala Gly Phe Asn Lys Ser Gly Ile Tyr Thr Ile Tyr Ile Asn Asn Met CCA GAA CCC AAA AAG GTG TTT TGC AAT ATG GAT GTC AAT GGG

Pro Glu Pro Lys Lys Val Phe Cys Asn Met Asp Val Asn Gly Gly Gly TGG ACT GTA ATA CAA CAT CGT GAA GAT GGA AGT CTA GAT TTC CAA

Trp Thr Val Ile Gln His Arg Glu Asp Gly Ser Leu Asp Phe Gln Arg GGC TGG AAG GAA TAT AAA ATG GGT TTT GGA AAT CCC TCC GGT

Gly Trp Lys Glu Tyr Lys Met Gly Phe Gly Asn Pro Ser Gly Glu Tyr TGG CTG GGG AAT GAG TTT ATT TTT GCC ATT ACC AGT CAG AGG CAG

Trp Leu Gly Asn Glu Phe Ile Phe Ala Ile Thr Ser Gln Arg Gln Tyr ATG CTA AGA ATT GAG TTA ATG GAC TGG GAA GGG AAC CGA GCC

Met Leu Arg Iie Glu Leu Met Asp Trp Giu Gly Asn Arg Ala Tyr Ser CAG TAT GAC AGA TTC CAC ATA GGA AAT GAA AAG CAA AAC TAT

Gln Tyr Asp Ara Phe His Ile Gly Asn Glu Lys Gln Asn Tyr Arg Leu TAT TTA AAA GGT CAC ACT GGG ACA GCA GGA AAA CAG AGC AGC

Tyr Leu Lys Gly His Thr Gly Thr Ala Gly Lys Gln Ser Ser Leu Ile 405 ' 410 , 415 TTA CAC GGT GCT GAT TTC AGC ACT AAA GAT GCT GAT AAT GAC AAC

Leu His Gly Ala Asp Phe Ser Thr Lys Asp Ala Asp Asn Asp Asn Cys ATG TGC AAA TGT GCC CTC ATG TTA ACA GGA GGA TGG 2'GG TTT GAT

Met Cys Lys Cys Ala Leu Met Leu Thr Gly Gly Trp Trp Phe Asp Ala TGT GGC CCC TCC AAT CTA AAT GGA ATG TTC TAT ACT GCG GGA CAA

Cys Gly Pro Ser Asn Leu Asn Gly Met Phe Tyr Thr Ala Gly Gln Asn CAT GGA AAA CTG AAT GGG ATA AAG TGG CAC TAC TTC AAA GGG

His Gly Lys Leu Asn Gly Ile Lys Trp His Tyr Phe Lys Gly Pro Ser TAC TCC TTA CGT TCC ACA ACT ATG ATG ATT CGA CCT TTA GAT TTT

Tyr Ser Leu Arg Ser Thr Thr Met Met Ile Arg Pro Leu Asp Phe (2) INFORMATION FOR SEQ ID NO:26:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 495 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (v) FRAGMENT TYPE: internal (ix) FEATURE:

(A) NAME/KEY: 2N1C1F (chimera 4) (B) LOCATION: 1...495 (D) OTHER INFORMATION:

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:26:

Met Trp Gln Ile Val Phe Phe Thr Leu Ser Cys Asp Leu Val Leu Ala Ala Ala Tyr Asn Asn Phe Arg Lys Ser Met Asp Ser Ile Gly Lys Lys Gln Tyr Gln Val Gln His Gly Ser Cys Ser Tyr Thr Phe Leu Leu Pro Glu Met Asp Asn Cys Arg Ser Ser Ser Ser Pro Tyr Val Ser Asn Ala Val Gln Arg Asp Ala Pro Leu Glu Tyr Asp Phe Ser Ser Gln Lys Leu Gln His Leu Glu His Val Met Glu Asn Tyr Thr Gin Trp Leu Gln Lys Leu Glu Asn Tyr Ile Val Glu Asn Met Lys Ser Glu Met Ala Gln Ile Gln Gln Asn Ala Val Gln Asn His Thr Ala Thr Met Leu Glu Ile Gly Thr Ser Leu Leu Ser Gln Thr Ala Glu Gln Thr Arg Lys Leu Thr Asp Val Glu Thr Gln Val Leu Asn Gln Thr Ser Arg Leu Glu Ile Gln Leu Leu Glu Asn Ser Leu Ser Tlir Tyr Lys Leu Glu Lys,Gln Leu Leu Gln Gln Thr Asn Glu Ile Leu Lys Ile His Giu Lys Asn Ser Leu Leu Glu His Lys Ile Leu Glu Met Glu Gly Lys His Lys Giu Giu Leu Asp Thr Leu Lys Glu Glu Lys Glu Asn Leu Gln Gly Leu Val Thr Arg G1n Thr 210 215 220 w Tyr Ile Ile Gln Glu Leu Glu Lys Gln Leu Asn Arg Ala Thr Thr Asn Asn Ser Val Leu Gln Lys Gln G1n Leu Glu Leu Met Asp Thr Val His Asn Leu Val Asn Leu Cys Thr Lys Glu Gly Val Leu Leu Lys Gly Gly Lys Arg Glu Glu Glu Lys Pro Phe Arg Asp Cys Ala Asp Val Tyr Gln Ala Gly Phe Asn Lys Ser Gly Ile Tyr Thr Ile Tyr Ile Asn Asn Met Pro Glu Pro Lys Lys Val Phe Cys Asn Met Asp Val Asn Gly Gly Gly Trp Thr Val Ile Gln His Arg Glu Asp Gly Ser Leu Asp Phe Gln Arg Gly Trp Lys Glu Tyr Lys Met Gly Phe Gly Asn Pro Ser Gly Glu Tyr Trp Leu Gly Asn Glu Phe Ile Phe Ala Ile Thr Ser Gln Arg Gln Tyr 355 360 365 , Met Leu Arg Ile Glu Leu Met Asp Trp Glu Gly Asn Arg Ala Tyr Ser Gin Tyr Asp Arg Phe His Ile Gly Asn Glu Lys Gin Asn Tyr Arg Leu Tyr Leu Lys Gly His Thr Gly Thr Ala Gly Lys Gin Ser Ser Leu Ile Leu His Giy Ala Asp Phe Ser Thr Lys Asp Ala Asp Asn Asp Asn Cys Met Cys Lys Cys Ala Leu Met Leu Thr Gly Gly Trp Trp Phe Asp Ala Cys Gly Pro Ser Asn Leu Asn Gly Met Phe Tyr Thr Ala Gly Gln Asn His Gly Lys Leu Asn Gly Ile Lys Trp His Tyr Phe Lys Gly Pro Ser Tyr Ser Leu Arg Ser Thr Thr Met Met Ile Arg Pro Leu Asp Phe (2) INFORMATION FOR SEQ ID NO:27:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 47 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA
(ix) FEATURE:

(A) NAME/KEY: hTL4atg (B) LOCATION: 1...47 (D) OTHER INFORMATION: PCR primer (A) NAME/KEY: Other (B) LOCATION: 1...20, (D) OTHER INFORMA'"ION: "tail" seauences added tc PCR primer to tacilitate 'i.orinc of the amplified PCR fragments (xi) SEQUENCE DESCRIPTION: SEQ ID NO:27:
~
GCATGCTATC TCGAGCCACC ATGCTCTCCC AGCTAGCCAT GCTGCAG

(2) INFORMATION FOR SEQ ID NO:28:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 55 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA
(ix) FEATURE:

(A) NAME/KEY: hTL4not (B) LOCATION: 1...55 (D) OTHER INFORMATION: PCR Primer (A) NAME/KEY: Other (B) LOCATION: 1...28 (D) OTHER INFORMATION: "tail" sequence added to the PCR primers to facilitate cloning of the amplified PCR fragments (xi) SEQUENCE DESCRIPTION: SEQ ID NO:28:
GTGTCGACGC GGCCGCTCTA GATCAGACTT AGATGTCCAA

D EMA1' dDES OU BREVETS VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DENIL,~NDE OU CE BREVETS
COIYTPREND PLUS D'U-N T IYIE.

CECI EST LE TOME

NOTE: Pour les tomes additioneis, veillez contacter le Bureau Canadien des Brevets.
J-U~~~O APPLICATIONS ~ PATENTS

THIS SECTION OF THE APPLICATION / PATENT CONT AINS 1vbORE
THAN ONE VOLUME.

-,~
THIS IS VOLUIVLE <77- OF '''~NOTE: For additional volumes please contact the Canadian Patent Office.

Claims (22)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:
1. ~An isolated nucleic acid molecule encoding a modified TIE-2 ligand that binds but does not activate TIE-2 receptor comprising a nucleotide sequence encoding TIE-2 ligand 1 wherein the portion of the nucleotide sequence that encodes the N-terminal domain of TIE-2 ligand 1 is deleted, the portion of the nucleotide sequence that encodes the coiled-coil domain of TIE-2 ligand 1 is deleted and the portion encoding the fibrinogen-like domain is fused in-frame to a nucleotide sequence encoding a human immunoglobulin gamma-1 constant region (IgG1 Fc).
2. ~A chimeric or modified TIE-2 ligand encoded by a nucleic acid molecule of claim 1.
3. ~A vector which comprises a nucleic acid molecule of claim 1 or 2.
4. ~A vector according to claim 3, wherein the nucleic acid molecule is operatively linked to an expression control sequence capable of directing its expression in a host cell.
5. ~A vector according to claim 3 or 4 which is a plasmid.
6. ~A host-vector system for the production of a chimeric or modified ligand according to claim 2 which comprises a vector according to any one of claims 3, 4 or 5.
7. ~A host-vector system according to claim 6 wherein the host cell is a bacterial, yeast, insect or mammalian cell.
8. ~A method of producing a ligand as defined in claim 2, which comprises growing cells of a host-vector system according to claim 6 or 7, under conditions permitting production of the ligand and recovering the ligand so produced.
9. An antibody which specifically binds the ligand of claim 2.
10. An antibody according to claim 9 which is a monoclonal antibody.
11. A receptorbody which specifically binds the ligand of claim 2.
12. An isolated nucleic acid molecule encoding a receptorbody according to claim 11.
13. A vector comprising a nucleic acid molecule according to claim 12.
14. A vector according to claim 13 which is a plasmid.
15. A conjugate comprising a ligand according to claim 2 and conjugated thereto, a cytotoxic agent.
16. A conjugate according to claim 15 wherein the cytotoxic agent is a radioisotope or toxin.
17. A pharmaceutical composition comprising a chimeric or modified ligand according to claim 2 and a pharmaceutically acceptable carrier.
18. A pharmaceutical composition comprising an antibody according to claim 9 or 10 and a pharmaceutically acceptable carrier.
19. A pharmaceutical composition comprising a receptorbody according to claim 11 and a pharmaceutically acceptable carrier.
20. A pharmaceutical composition comprising a conjugate according to claim 15 or 16 and a pharmaceutically acceptable carrier.
21. A ligand according to claim 2, an antibody according to claim 9 or 10, a receptorbody according to claim 11 or a conjugate according to claim 15 or 16 for use in a method of treatment of the human or animal body, or in a method of diagnosis.
22. ~A ligand produced by the method of claim 8.
CA002595037A 1996-08-02 1997-08-01 Modified tie-2 receptor ligands Abandoned CA2595037A1 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US2299996P 1996-08-02 1996-08-02
US60/022,999 1996-08-02
US08/740,223 US6265564B1 (en) 1996-08-02 1996-10-25 Expressed ligand-vascular intercellular signalling molecule
US08/740,223 1996-10-25
CA002262409A CA2262409C (en) 1996-08-02 1997-08-01 Modified tie-2-receptor ligands

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
CA002262409A Division CA2262409C (en) 1996-08-02 1997-08-01 Modified tie-2-receptor ligands

Publications (1)

Publication Number Publication Date
CA2595037A1 true CA2595037A1 (en) 1998-02-12

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Family Applications (2)

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CA002595037A Abandoned CA2595037A1 (en) 1996-08-02 1997-08-01 Modified tie-2 receptor ligands
CA2595038A Expired - Lifetime CA2595038C (en) 1996-08-02 1997-08-01 Modified tie-2 receptor ligands

Family Applications After (1)

Application Number Title Priority Date Filing Date
CA2595038A Expired - Lifetime CA2595038C (en) 1996-08-02 1997-08-01 Modified tie-2 receptor ligands

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Also Published As

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CA2595038A1 (en) 1998-02-12
CA2595038C (en) 2012-10-30

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