Circular permuteins of flt3 ligand

• US 6,660,257 B1
• Filed: 10/21/1997
• Issued: 12/09/2003
• Est. Priority Date: 10/25/1996
• Status: Expired due to Fees

• Current Assignee: GD Searle LLC (Pfizer Inc.)
• Original Assignee: Pharmacia Corporation (Pfizer Inc.)
• Inventors: Streeter, Philip R., Woulfe, Susan L., Minster, Nancy I., Mc Kearn, John P., Minnerly, John C., Feng, Yiqing, McWherter, Charles A., Staten, Nicholas R.
• Primary Examiner(s): KUNZ, GARY L
• Application Number:
  US08/955,090
• Time in Patent Office: 2,240 Days
• Field of Search: 435/69.5, 435/69.7, 435/325, 435/360, 435/365.1, 435/252.3, 435/320.1, 530/350, 530/351, 530/399, 536/23.1, 536/23.4, 935/10, 935/13, 424/85.1, 424/192.1, 424/198.1, 514/2, 514/12
• US Class Current: 424/85.1
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61P 7/06 Antianaemics
• CPC Class Codes: C07K 14/475 Growth factors; Growth regulators

Abstract

Disclosed are novel flt-3 receptor agonist proteins, DNAs which encode the flt-3 receptor agonist proteins, methods of making the flt-3 receptor agonist proteins and methods of using the flt-3 receptor agonist proteins.

Claims

1. A human flt-3 receptor agonist polypeptide, comprising a modified flt-3 ligand amino acid sequence selected from the group consisting of:

(a) the sequence of SEQ ID NO;

144; and

(b) a polypeptide comprising residues 1-132 of SEQ ID NO;

144;

wherein said modification comprises the linear rearrangement of the sequences of (a) or (b);

wherein the N-terminus is joined to the C-terminus directly or through a linker capable of joining the N-terminus to the C-terminus and new C- and N-termini are created between the amino acid residue pairs of SEQ ID NO;

144 selected from the group consisting of;

28-29, 29-30, 30-31, 31-32, 32-33, 34-35, 36-37, 37-38, 38-39, 40-41, 41-42, 42-43, 64-65, 65-66, 66-67, 86-87, 88-89, 89-90, 90-91, 91-92, 92-93, 93-94, 94-95, 95-96, 96-97, 97-98, 98-99, 99-100, 100-101, 101-102, and 102-103; and

wherein optionally said flt-3 receptor agonist polypeptide is immediately preceded by (methionine<sup>−

1</sup>), (alanine<sup>−

1</sup>) or (methionine<sup>−

2</sup>, alanine<sup>−

1</sup>).

2. The flt-3 receptor agonist polypeptide, as recited in claim 1, wherein said linker is selected from the group consisting of;

GlyGlyGlySer SEQ ID NO;

38;

GlyGlyGlySerGlyGlyGlySer SEQ ID NO;

39;

GlyGlyGlySerGlyGlyGlySerGlyGlyGlySer SEQ ID NO;

40;

SerGlyGlySerGlyGlySer SEQ ID NO;

41;

GluPheGlyAsnMet SEQ ID NO;

42;

GluPheGlyGlyAsriMet SEQ ID NO;

43;

GluPheGlyGlyAsnGlyGlyAsnMet SEQ ID NO;

443

GlyGlySerAspMetAlaGly SEQ ID NO;

45;

SerGlyGlyAsnGly SEQ ID NO;

46;

SerGlyGlyAsnGlySerGlyGlyAsnGly SEQ ID NO;

47;

SerGlyGlyAsnGlySerGlyGlyAsnGlySerGlyGlyAsnGly SEQ ID NO;

48;

SerGlyGlySerGlySerGlyGlySerGly SEQ ID NO;

49;

SerGlyGlySerGlySerGlyGlySerGlySerGlyGlySerGly SEQ ID NO;

50;

GlyGlyGlySerGlyGly SEQ ID NO;

51;

GlyGlyGlySerGlyGlyGly SEQ ID NO;

52;

GlyGlyGlySerGlyGlyGlySerGlyGly SEQ ID NO;

53;

GlyGlyGlySerGlyGlyGlySerGlyGlyGlySerGly SEQ ID NO;

54;

GlyGlyGlySerGlyGlyGlySerGlyGlyGlySerGlyGlyGly SEQ ID NO;

55;

GlyGlyGlySerGlyGlyGlySerGlyGlyGlySerGlyGlyGlySerGly GlyGlySerGly SEQ ID NO;

56;

GlyGlyGlySerGlyGlyGlySerGlyGlyGlySerGlyGlyGlySerGly GlyGlySerGlyGlyGlySerGlyGlyGlySerGly SEQ ID NO;

148;

ProProProTrpSerProArgProLeuGlyAlaThrAlaProThrAlaGly GlnProProLeu SEQ ID NO;

149;

ProProProTrpSerProArgProLeuGlyAlaThrAlaProThr SEQ ID NO;

150; and

ValGluThrValPheHisArgValSerGlnAspGlyLeuLeuThrSer SEQ ID NO;

151.

3. The flt-3 receptor agonist polypeptide, as recited in claim 1, selected from the group consisting of;

AlaAspGluGluLeuCysGlyGlyLeuTrpArgLeuValLeuAlaGlnArgTrpMETGlu ArgLeuLysThrValAlaGlySerLysMETGlnGlyLeuLeuGluArgValAsnThrGlu IleHisPheValThrLysCysAlaPheGlnProProProSerCysLeuArgpheValGln ThrAsnIleSerArgLeuLeuGlnGluThrSerGluGlnLeuValAlaLeuLysProTrp IleThrArgGlnAsnPheSerArgCysLeuGluLeuGlnCysGlnProAspSerSerThr LeuSerGlyGlyAsnGlySerGlyGlyAsnGlySerGlyGlyAsnGlyThrGlnAspCys SerPheGlnHisSerProIleSerSerAspPheAlaValLysIleArgGluLeuSerAsp TyrLeuLeuGlnAspTyrProValThrValAlaSerAsnLeuGln SEQ ID NO;

8;

AlaAspGluGluLeuCysGlyGlyLeuTrpArgLeuValLeuAlaGlnArgTrpMETGlu ArgLeuLysThrValAlaGlySerLysMETGlnGlyLeuLeuGluArgValAsnThrGlu IleHisPheValThrLysCysAlaPheGlnProProProSerCysLeuArgPheValGln ThrAsnIleSerArgLeuLeuGlnGluThrSerGluGlnLeuValAlaLeuLysProTrp IleThrArgGlnAsnPheSerArgCysLeuGluLeuGlnCysGlnProAspSerSerThr LeuSerGlyGlyAsnGlySerGlyGlyAsnGlyThrGlnAspCysSerPheGlnHisSer ProIleSerSerAspPheAlaValLysIleArgGluLeuSerAspTyrLeuLeuGlnAsp TyrProValThrValAlaSerAsnLeuGln SEQ ID NO;

9;

AlaAspGluGluLeuCysGlyGlyLeuTrpArgLeuValLeuAlaGlnArgTrpMETGlu ArgLeuLysThrValAlaGlySerLysMETGlnGlyLeuLeuGluArgValAsnThrGlu IleHisPheValThrLysCysAlaPheGlnProProProSerCysLeuArgpheValGln ThrAsnIleSerArgLeuLeuGlnGluThrSerGluGlnLeuValAlaLeuLysProTrp IleThrArgGlnAsnPheSerArgCysLeuGluLeuGlnCysGlnProAspSerSerThr LeuSerGlyGlyAsnGlyThrGlnAspCysSerPheGlnHisSerProIleSerSerAsp PheAlaValLysIleArgGluLeuSerAspTyrLeuLeuGlnAspTyrProValThrVal AlaSerAsnLeuGln SEQ ID NO;

10;

AlaSerLysMETGlnGlyLeuLeuGluArgValAsnThrGluIleHisPheValThrLys CysAlaPheGlnProProProSerCysLeuArgPheValGlnThrAsnIleSerArgLeu LeuGlnGluThrSerGluGlnLeuValAlaLeuLysProTrpIleThrArgGlnAsnPhe SerArgCysLeuGluLeuGlnCysGlnProAspSerSerThrLeuSerGlyGlyAsnGly SerGlyGlyAsnGlySerGlyGlyAsnGlyThrGlnAspCysSerPheGlnHisSerPro IleSerSerAspPheAlaValLysIleArgGluLeuSerAspTyrLeuLeuGlnAspTyr ProValThrValAlaSerAsnLeuGlnAspGluGluLeuCysGlyGlyLeuTrpArgLeu ValLeuAlaGlnArgTrpMETGluArgLeuLysThrValAlaGly SEQ ID NO;

11;

AlaSerLysMETGlnGlyLeuLeuGluArgValAsnThrGluIleHisPheValThrLys CysAlaPheGlnProProProSerCysLeuArgPheValGlnThrAsnIleSerArgLeu LeuGlnGluThrSerGluGlnLeuValAlaLeuLysProTrpIleThrArgGlnAsnphe SerArgCysLeuGluLeuGlnCysGlnProAspSerSerThrLeuSerGlyGlyAsnGly SerGlyGlyAsnGlyThrGlnAspCysSerPheGlnHisSerProIleSerSerAspphe AlaValLysIleArgGluLeuSerAspTyrLeuLeuGlnAspTyrProValThrValAla SerAsnLeuGlnAspGluGluLeuCysGlyGlyLeuTrpArgLeuValLeuAlaGlnArg TrpMETGluArgLeuLysThrValAlaGly SEQ ID NO;

12

AlaSerLysMETGlnGlyLeuLeuGluArgValAsnThrGluIleHisPheValThrLys CysAlaPheGlnProProProSerCysLeuArgPheValGlnThrAsnIleSerArgLeu LeuGlnGluThrSerGluGlnLeuValAlaLeuLysProTrpIleThrArgGlnAsnPhe SerArgCysLeuGluLeuGlnCysGlnProAspSerSerThrLeuSerGlyGlyAsnGly ThrGlnAspCysSerPheGlnHisSerProIleSerSerAspPheAlaValLysIleArg GluLeuSerAspTyrLeuLeuGlnAspTyrProValThrValAlaSerAsnLeuGlnAsp GluGluLeuCysGlyGlyLeuTrpArgLeuValLeuAlaGlnArgTrpMETGluArgLeu LysThrValAlaGly SEQ ID NO;

13;

AlaProProSerCysLeuArgPheValGlnThrAsnIleSerArgLeuLeuGlnGluThr SerGluGlnLeuValAlaLeuLysProTrpIleThrArgGlnAsnPheSerArgCysLeu GluLeuGlnCysGlnProAspSerSerThrLeuSerGlyGlyAsnGlySerGlyGlyAsn GlySerGlyGlyAsnGlyThrGlnAspCysSerPheGlnHisSerProIleSerSerAsp PheAlaValLysIleArgGluLeuSerAspTyrLeuLeuGlnAspTyrProValThrVal AlaSerAsnLeuGlnAspGluGluLeuCysGlyGlyLeuTrpArgLeuValLeuAlaGln ArgTrpMETGluArgLeuLysThrValAlaGlySerLysMETGlnGlyLeuLeuGluArg ValAsnThrGluIleHisPheValThrLysCysAlaPheGlnPro SEQ ID NO;

14;

AlaProProSerCysLeuArgPheValGlnThrAsnIleSerArgLeuLeuGlnGluThr SerGluGlnLeuValAlaLeuLysProTrpIleThrArgGlnAsnPheSerArgCysLeu GluLeuGlnCysGlnProAspSerSerThrLeuSerGlyGlyAsnGlySerGlyGlyAsn GlyThrGlnAspCysSerPheGlnHisSerProIleSerSerAspPheAlaValLysIle ArgGluLeuSerAspTyrLeuLeuGlnAspTyrProValThrValAlaSerAsnLeuGln AspGluGluLeuCysGlyGlyLeuTrpArgLeuValLeuAlaGlnArgTrpMETGluArg LeuLysThrValAlaGlySerLysMETGlnGlyLeuLeuGluArgValAsnThrGluIle HisPheValThrLysCysAlaPheGlnPro SEQ ID NO;

15;

AlaProProSerCysLeuArgPheValGlnThrAsnIleSerArgLeuLeuGlnGluThr SerGluGlnLeuValAlaLeuLysProTrpIleThrArgGlnAsnPheSerArgCysLeu GluLeuGlnCysGlnProAspSerSerThrLeuSerGlyGlyAsnGlyThrGlnAspCys SerPheGlnHisSerProIleSerSerAspPheAlaValLysIleArgGluLeuSerAsp TyrLeuLeuGlnAspTyrProValThrValAlaSerAsnLeuGlnAspGluGluLeuCys GlyGlyLeuTrpArgLeuValLeuAlaGlnArgTrpMETGluArgLeuLysThrValAla GlySerLysMETGlnGlyLeuLeuGluArgValAsnThrGluIleHisPheValThrLys CysAlaPheGlnPro SEQ ID NO;

16;

AlaAspTyrProValThrValAlaSerAsnLeuGlnAspGluGluLeuCysGlyGlyLeu TrpArgLeuValLeuAlaGlnArgTrpMetGluArgLeuLysThrValAlaGlySerLys MetGlnGlyLeuLeuGluArgValAsnThrGluIleHisPheValThrLysCysAlaPhe GlnProProProSerCysLeuArgPheValGlnThrAsnIleSerArgLeuLeuGlnGlu ThrSerGluGlnLeuValAlaLeuLysProTrpIleThrArgGlnAsnPheSerArgCys LeuGluLeuGlnCysGlnProAspSerSerThrLeuGlyGlyGlySerGlyGlyGlySer GlyGlyGlySerGlyGlyGlyThrGlnAspCysSerPheGlnHisSerProIleSerSer AspPheAlaValLysIleArgGluLeuSerAspTyrLeuLeuGln SEQ ID NO;

31;

AlaAlaSerAsnLeuGlnAspGluGluLeuCysGlyGlyLeuTrpArgLeuValLeuAla GlnArgTrpMetGluArgLeuLysThrValAlaGlySerLysMetGlnGlyLeuLeuGlu ArgvalAsnThrGluIleHisPheValThrLysCysAlaPheGlnProProProSerCys LeuArgPheValGlnThrAsnIleSerArgLeuLeuGlnGluThrSerGluGlnLeuVal AlaLeuLysProTrpIleThrArgGlnAsnPheSerArgCysLeuGluLeuGlnCysGln ProAspSerSerThrLeuGlyGlyGlySerGlyGlyGlySerGlyGlyGlySerGlyGly GlyThrGlnAspCysSerPheGlnHisSerProIleSerSerAspPheAlaValLysIle ArgGluLeuSerAspTyrLeuLeuGlnAspTyrProValThrVal SEQ ID NO;

32;

AlaValAlaGlySerLysMetGlnGlyLeuLeuGluArgValAsnThrGluIleHisPhe ValThrLysCysAlaPheGlnProProProSerCysLeuArgPheValGlnThrAsnIle SerArgLeuLeuGlnGluThrSerGluGlnLeuValAlaLeuLysProTrpIleThrArg GlnAsnPheSerArgCysLeuGluLeuGlnCysGlnProAspSerSerThrLeuGlyGly GlySerGlyGlyGlySerGlyGlyGlySerGlyGlyGlyThrGlnAspCysSerPheGln HisSerProIleSerSerAspPheAlaValLysIleArgGluLeuSerAspTyrLeuLeu GlnAspTyrProValThrValAlaSerAsnLeuGlnAspGluGluLeuCysGlyGlyLeu TrpArgLeuValLeuAlaGlnArgTrpMetGluArgLeuLysThr SEQ ID NO;

33;

AlaSerLysMetGlnGlyLeuLeuGluArgValAsnThrGluIleHisPheValThrLys CysAlaPheGlnProProProSerCysLeuArgPhevalGlnThrAsnIleSerArgLeu LeuGlnGluThrSerGluGlnLeuValAlaLeuLysProTrpIleThrArgGlnAsnPhe SerArgCysLeuGluLeuGlnCysGlnProAspSerSerThrLeuGlyGlyGlySerGly GlyGlySerGlyGlyGlySerGlyGlyGlyThrGlnAspCysSerPheGlnHisSerPro IleSerSerAspPheAlaValLysIleArgGluLeuSerAspTyrLeuLeuGlnAspTyr ProValThrValAlaSerAsnLeuGlnAspGluGluLeuCysGlyGlyLeuTrpArgLeu ValLeuAlaGlnArgTrpMetGluArgLeuLysThrValAlaGly SEQ ID NO;

34;

AlaProProSerCysLeuArgPheValGlnThrAsnIleSerArgLeuLeuGlnGluThr SerGluGlnLeuValAlaLeuLysProTrpIleThrArgGlnAsnPheSerArgCysLeu GluLeuGlnCysGlnProAspSerSerThrLeuGlyGlyGlySerGlyGlyGlySerGly GlyGlySerGlyGlyGlyThrGlnAspCysSerPheGlnHisSerProIleSerSerAsp PheAlaValLysIleArgGluLeuSerAspTyrLeuLeuGlnAspTyrProValThrVal AlaSerAsnLeuGlnAspGluGluLeuCysGlyGlyLeuTrpArgLeuValLeuAlaGln ArgTrpMetGluArgLeuLysThrValAlaGlySerLysMetGlnGlyLeuLeuGluArg ValAsnThrGluIleHisPheValThrLysCysAlaPheGlnPro SEQ ID NO;

35;

AlaArgPheValGlnThrAsnIleSerArgLeuLeuGlnGluThrSerGluGlnLeuVal AlaLeuLysProTrpIleThrArgGlnAsnPheSerArgCysLeuGluLeuGlnCysGln ProAspSerSerThrLeuGlyGlyGlySerGlyClyGlySerGlyGlyGlySerGlyGly GlyThrGlnAspCysSerPheGlnHisSerProIleSerSerAspPheAlaValLysIle ArgGluLeuSerAspTyrLeuLeuGlnAspTyrProValThrValAlaSerAsnLeuGln AspGluGluLeuCysGlyGlyLeuTrpArgLeuValLeuAlaGlnArgTrpMetGluArg LeuLysThrValAlaGlySerLysMetGlnGlyLeuLeuGluArgValAsnThrGluIle HisPheValThrLysCysAlaPheGlnProProProSerCysLeu SEQ ID NO;

36;

AlaThrAsnIleSerArgLeuLeuGlnGluThrSerGluGlnLeuValAlaLeuLysPro TrpIleThrArgGlnAsnPheSerArgCysLeuGluLeuGlnCysGlnProAspSerSer ThrLeuGlyGlyGlySerGlyGlyGlySerGlyGlyGlySerGlyGlyGlyThrGlnAsp CysSerPheGlnHisSerProIleSerSerAspPheAlaValLysIleArgGluLeuSer AspTyrLeuLeuGlnAspTyrProValThrValAlaSerAsnLeuGlnAspGluGluLeu CysGlyGlyLeuTrpArgLeuValLeuAlaGlnArgTrpMetGluArgLeuLysThrVal AlaGlySerLysMetGlnGlyLeuLeuGluArgValAsnThrGluIleHisPheValThr LysCysAlaPheGlnProProProSerCysLeuArgPheValGln SEQ ID NO;

37.

4. A nucleic acid molecule, comprising a sequence encoding the flt-3 receptor agonist polypeptide of claim 1.

5. A nucleic acid molecule, comprising a sequence encoding the flt-3 receptor agonist polypeptide of claim 2.

6. A nucleic acid molecule, comprising a sequence encoding the flt-3 receptor agonist polypeptide of claim 3.

7. A nucleic acid molecule, comprising a sequence encoding the flt-3 receptor agonist polypeptide of claim 6, selected from the group consisting of:

GCCGACGAGGAGCTCTGCGGGGGCCTCTGGCGGCTGGTCCTGGCACAGCG CTGGATGGAGCGGCTCAAGACTGTCGCTGGGTCCAAGATGCAAGGCTTGC TGGAGCGCGTGAACACGGAGATACACTTTGTCACCAAATGTGCCTTTCAG CCCCCCCCCAGCTGTCTTCGCTTCGTCCAGACCAACATCTCCCGCCTCCT GCAGGAGACCTCCGAGCAGCTGGTGGCGCTGAAGCCCTGGATCACTCGCC AGAACTTCTCCCGGTGCCTGGAGCTGCAGTGTCAGCCCGACTCCTCAACC CTGTCTGGAGGTAACGGATCCGGTGGCAATGGGAGCGGCGGAAATGGAAC CCAGGACTGCTCCTTCCAACACAGCCCCATCTCCTCCGACTTCGCTGTCA AAATCCGTGAGCTGTCTGACTACCTGCTTCAAGATTACCCAGTCACCGTG GCCTCCAACCTGCAG SEQ ID NO;

113;

GCCGACGAGGAGCTCTGCGGGGGCCTCTGGCGGCTGGTCCTGGCACAGCG CTGGATGGAGCGGCTCAAGACTGTCGCTGGGTCCAAGATGCAAGGCTTGC TGGAGCGCGTGAACACGGAGATACACTTTGTCACCAAATGTGCCTTTCAG CCCCCCCCCAGCTGTCTTCGCTTCGTCCAGACCAACATCTCCCGCCTCCT GCAGGAGACCTCCGAGCAGCTGGTGGCGCTGAAGCCCTGGATCACTCGCC AGAACTTCTCCCGGTGCCTGGAGCTGCAGTGTCAGCCCGACTCCTCAACC CTGTCAGGCGGTAACGGCAGTGGAGGTAATGGCACCCAGGACTGCTCCTT CCAACACAGCCCCATCTCCTCCGACTTCGCTGTCAAAATCCGTGAGCTGT CTGACTACCTGCTTCAAGATTACCCAGTCACCGTGGCCTCCAACCTGCAG SEQ ID NO;

114;

GCCGACGAGGAGCTCTGCGGGGGCCTCTGGCGGCTGGTCCTGGCACAGCG CTGGATGGAGCGGCTCAAGACTGTCGCTGGGTCCAAGATGCAAGGCTTGC TGGAGCGCGTGAACACGGAGATACACTTTGTCACCAAATGTGCCTTTCAG CCCCCCCCCAGCTGTCTTCGCTTCGTCCAGACCAACATCTCCCGCCTCCT GCAGGAGACCTCCGAGCAGCTGGTGGCGCTGAAGCCCTGGATCACTCGCC AGAACTTCTCCCGGTGCCTGGAGCTGCAGTGTCAGCCCGACTCCTCAACC CTGTCTGGCGGCAACGGCACCCAGGACTGCTCCTTCCAACACAGCCCCAT CTCCTCCGACTTCGCTGTCAAAATCCGTGAGCTGTCTGACTACCTGCTTC AAGATTACCCAGTCACCGTGGCCTCCAACCTGCAG SEQ ID NO;

115;

GCCTCCAAGATGCAAGGCTTGCTGGAGCGCGTGAACACGGAGATACACTT TGTCACCAAATGTGCCTTTCAGCCCCCCCCCAGCTGTCTTCGCTTCGTCC AGACCAACATCTCCCGCCTCCTGCAGGAGACCTCCGAGCAGCTGGTGGCG CTGAAGCCCTGGATCACTCGCCAGAACTTCTCCCGGTGCCTGGAGCTGCA GTGTCAGCCCGACTCCTCAACCCTGTCTGGAGGTAACGGATCCGGTGGCA ATGGGAGCGGCGGAAATGGAACCCAGGACTGCTCCTTCCAACACAGCCCC ATCTCCTCCGACTTCGCTGTCAAAATCCGTGAGCTGTCTGACTACCTGCT TCAAGATTACCCAGTCACCGTGGCCTCCAACCTGCAGGACGAGGAGCTCT GCGGGGGCCTCTGGCGGCTGGTCCTGGCACAGCGCTGGATGGAGCGGCTC AAGACTGTCGCTGGG SEQ ID NO;

116;

GCCTCCAAGATGCAAGGCTTGCTGGAGCGCGTGAACACGGAGATACACTT TGTCACCAAATGTGCCTTTCAGCCCCCCCCCAGCTGTCTTCGCTTCGTCC AGACCAACATCTCCCGCCTCCTGCAGGAGACCTCCGAGCAGCTGGTGGCG CTGAAGCCCTGGATCACTCGCCAGAACTTCTCCCGGTGCCTGGAGCTGCA GTGTCAGCCCGACTCCTCAACCCTGTCTGGAGGTAACGGATCCGGAGGTA ATGGCACCCAGGACTGCTCCTTCCAACACAGCCCCATCTCCTCCGACTTC GCTGTCAAAATCCGTGAGCTGTCTGACTACCTGCTTCAAGATTACCCAGT CACCGTGGCCTCCAACCTGCAGGACGAGGAGCTCTGCGGGGGCCTCTGGC GGCTGGTCCTGGCACAGCGCTGGATGGAGCGGCTCAAGACTGTCGCTGGG SEQ ID NO;

117;

GCCTCCAAGATGCAAGGCTTGCTGGAGCGCGTGAACACGGAGATACACTT TGTCACCAAATGTGCCTTTCAGCCCCCCCCCAGCTGTCTTCGCTTCGTCC AGACCAACATCTCCCGCCTCCTGCAGGAGACCTCCGAGCAGCTGGTGGCG CTGAAGCCCTGGATCACTCGCCAGAACTTCTCCCGGTGCCTGGAGCTGCA GTGTCAGCCCGACTCCTCAACCCTGTCTGGCGGCAACGGCACGCAGGACT GCTCCTTCCAACACAGCCCCATCTCCTCCGACTTCGCTGTCAAAATCCGT GAGCTGTCTGACTACCTGCTTCAAGATTACCCAGTCACCGTGGCCTCCAA CCTGCAGGACGAGGAGCTCTGCGGGGGCCTCTGGCGGCTGGTCCTGGCAC AGCGCTGGATGGAGCGGCTCAAGACTGTCGCTGGG SEQ ID NO;

118;

GCCCCCCCCAGCTGTCTTCGCTTCGTCCAGACCAACATCTCCCGCCTCCT GCAGGAGACCTCCGAGCAGCTGGTGGCGCTGAAGCCCTGGATCACTCGCC AGAACTTCTCCCGGTGCCTGGAGCTGCAGTGTCAGCCCGACTCCTCAACC CTGTCTGGAGGTAACGGCAGTGGTGGCAATGGGAGCGGTGGAAATGGAAC CCAGGACTGCTCCTTCCAACACAGCCCCATCTCCTCCGACTTCGCTGTCA AAATCCGTGAGCTGTCTGACTACCTGCTTCAAGATTACCCAGTCACCGTG GCCTCCAACCTGCAGGACGAGGAGCTCTGCGGGGGCCTCTGGCGGCTGGT CCTGGCACAGCGCTGGATGGAGCGGCTCAAGACTGTCGCTGGGTCCAAGA TGCAAGGCTTGCTGGAGCGCGTGAACACGGAGATACACTTTGTCACCAAA TGTGCCTTTCAGCCC SEQ ID NO;

119;

GCCCCCCCCAGCTGTCTTCGCTTCGTCCAGACCAACATCTCCCGCCTCCT GCAGGAGACCTCCGAGCAGCTGGTGGCGCTGAAGCCCTGGATCACTCGCC AGAACTTCTCCCGGTGCCTGGAGCTGCAGTGTCAGCCCGACTCCTCAACC CTGTCAGGCGGTAACGGCAGTGGAGGTAATGGCACCCAGGACTGCTCCTT CCAACACAGCCCCATCTCCTCCGACTTCGCTGTCAAAATCCGTGAGCTGT CTGACTACCTGCTTCAAGATTACCCAGTCACCGTGGCCTCCAACCTGCAG GACGAGGAGCTCTGCGGGGGCCTCTGGCGGCTGGTCCTGGCACAGCGCTG

GATGGAGCGGCTCAAGACTGTCGCTGGGTCCAAGATGCAAGGCTTGCTGG AGCGCGTGAACACGGAGATACACTTTGTCACCAAATGTGCCTTTCAGCCC SEQ ID NO;

120;

GCCCCCCCCAGCTGTCTTCGCTTCGTCCAGACCAACATCTCCCGCCTCCT GCAGGAGACCTCCGAGCAGCTGGTGGCGCTGAAGCCCTGGATCACTCGCC AGAACTTCTCCCGGTGCCTGGAGCTGCAGTGTCAGCCCGACTCCTCAACC CTGTCTGGCGGCAACGGCACGCAGGACTGCTCCTTCCAACACAGCCCCAT CTCCTCCGACTTCGCTGTCAAAATCCGTGAGCTGTCTGACTACCTGCTTC AAGATTACCCAGTCACCGTGGCCTCCAACCTGCAGGACGAGGAGCTCTGC GGGGGCCTCTGGCGGCTGGTCCTGGCACAGCGCTGGATGGAGCGGCTCAA GACTGTCGCTGGGTCCAAGATGCAAGGCTTGCTGGAGCGCGTGAACACGG AGATACACTTTGTCACCAAATGTGCCTTTCAGCCC SEQ ID NO;

121;

GCCGATTACCCAGTCACCGTGGCCTCCAACCTGCAGGACGAGGAGCCTGCCGGGG GCCTCTGGCGGCTGGTCCTGGCACAGCGCTGGATGGAGCGGCTCAAGACTGTCGC TGGGTCCAAGATGCAAGGCTTGCTGGAGCGCGTGAACACGGAGATACACTTTGTC ACCAAATGTGCCTTTCAGCCCCCCCCCAGCTGTCTTCGCTTCGTCCAGACCAACA TCTCCCGCCTCCTGCAGGAGACCTCCGAGCAGCTGGTGGCGCTGAAGCCCTGGAT CACTCGCCAGAACTTCTCCCGGTGCCTGGAGCTGCAGTGTCAGCCCGACTCCTCA ACCCTGGGCGGTGGGTCAGGAGGTGGGTCAGGAGGTGGATCCGGAGGTGGCACCC AGGACTGCTCCTTCCAACACAGCCCCATCTCCTCCGACTTCGCTGTCAAAATCCG TGAGCTGTCTGACTACCTGCTTCAA SEQ ID NO;

136;

GCCGCCTCCAACCTGCAGGACGAGGAGCTCTGCGGGGGCCTCTGGCGGCTGGTCC TGGCACAGCGCTGGATGGAGCGGCTCAAGACTGTCGCTGGGTCCAAGATGCAAGG CTTGCTGGAGCGCGTGAACACGGAGATACACTTTGTCACCAAAATGTGCCTTTCAG CCCCCCCCCAGCTGTCTTCGCTTCGTCCAGACCAACATCTCCCGCCTCCTGCAGG AGACCTCCGAGCAGCTGGTGGCGCTGAAGCCCTGGATCACTCGCCAGAACTTCTC CCGGTGCCTGGAGCTGCAGTGTCAGCCCGACTCCTCAACCCTGGGCGGTGGGTCA GGAGGTGGGTCAGGAGGTGGATCCGGAGGTGGCACCCAGGACTGCTCCTTCCAAC ACAGCCCCATCTCCTCCGACTTCGCTGTCAAAATCCGTGAGCTGTCTGACTACCT GCTTCAAGATTACCCAGTCACCGTG SEQ ID NO;

137;

GCCGTCGCTGGGTCCAAGATGCAAGGCTTGCTGGAGCGCGTGAACACGGAGATAC ACTTTGTCACCAAATGTGCCTTTCAGCCCCCCCCCAGCTGTCTTCGCTTCGTCCA GACCAACATCTCCCGCCTCCTGCAGGAGACCTCCGAGCAGCTGGTGGCGCTGAAG CCCTGGATCACTCGCCAGAACTTCTCCCGGTGCCTGGAGCTGCAGTGTCAGCCCG ACTCCTCAACCCTGGGCGGTGGGTCAGGAGGTGGGTCAGGAGGTGGATCCGGAGG TGGCACCCAGGACTGCTCCTTCCAACACAGCCCCATCTCCTCCGACTTCGCTGTC AAAATCCGTGAGCTGTCTGACTACCTGCTTCAAGATTACCCAGTCACCGTGGCCT CCAACCTGCAGGACGAGGAGCTCTGCGGGGGCCTCTGGCGGCTGGTCCTGGCACA GCGCTGGATGGAGCGGCTCAAGACT SEQ ID NO;

138;

GCCTCCAAGATGCAAGGCTTGCTGGAGCGCGTGAACACGGAGATACACTTTGTCA CCAAATGTGCCTTTCAGCCcCCCCCCCAGCTGTCTTCGCTTCGTCCAGACCAACAT CTCCCGCCTCCTGCAGGAGACCTCCGAGCAGCTGGTGGCGCTGAAGCCCTGGATC ACTCGCCAGAACTTCTCCCGGTGCCTGGAGCTGCAGTGTCAGCCCGACTCCTCAA CCCTGGGCGGTGGGTCAGGAGGTGGGTCAGGAGGTGGATCCGGAGGTGGCACCCA GGACTGCTCCTTCCAACACAGCCCCATCTCCTCCGACTTCGCTGTCAAAATCCGT GAGCTGTCTGACTACCTGCTTCAAGATTACCCAGTCACCGTGGCCTCCAACCTGC AGGACGAGGAGCTCTGCGGGGGCCTCTGGCGGCTGGTCCTGGCACAGCGCTGGAT GGAGCGGCTCAAGACTGTCGCTGGG SEQ ID NO;

139;

GCCCCCCCCAGCTGTCTTCGCTTCGTCCAGACCAACATCTCCCGCCTCCTGCAGG AGACCTCCGAGCAGCTGGTGGCGCTGAAGCCCTGGATCACTCGCCAGAACTTCTC CCGGTGCCTGGAGCTGCAGTGTCAGCCCGACTCCTCAACCCTGGGCGGTGGGTCA GGAGGTGGGTCAGGAGGTGGATCCGGAGGTGGCACCCAGGACTGCTCCTTCCAAC ACAGCCCCATCTCCTCCGACTTCGCTGTCAAAATCCGTGAGCTGTCTGACTACCT GCTTCAAGATTACCCAGTCACCGTGGCCTCCAACCTGCAGGACGAGGAGCTCTGC GGGGGCCTCTGGCGGCTGGTCCTGGCACAGCGCTGGATGGAGCGGCTCAAGACTG TCGCTGGGTCCAAGATGCAAGGCTTGCTGGAGCGCGTGAACACGGAGATACACTT TGTCACCAAATGTGCCTTTCAGCCC SEQ ID NO;

140;

GCCCGCTTCGTCCAGACCAACATCTCCCGCCTCCTGCAGGAGACCTCCGAGCAGC TGGTGGCGCTGAAGCCCTGGATCACTCGCCAGAACTTCTCCCGGTGCCTGGAGCT GCAGTGTCAGCCCGACTCCTCAACCCTGGGCGGTGGGTCAGGAGGTGGGTCAGGA GGTGGATCCGGAGGTGGCACCCAGGACTGCTCCTTCCAACACAGCCCCATCTCCT CCGACTTCGCTGTCAAAATCCGTGAGCTGTCTGACTACCTGCTTCAAGATTACCC AGTCACCGTGGCCTCCAACCTGCAGGACGAGGAGCTCTGCGGGGGCCTCTGGCGG CTGGTCCTGGCACAGCGCTGGATGGAGCGGCTCAAGACTGTCGCTGGGTCCAAGA rTGCAAGGCTTGCTGGAGCGCGTGAACACGGAGATACACTTTGTCACCAAATGTGC CTTTCAGCCCCCCCCCAGCTGTCTT SEQ ID NO;

142;

GCCACCAACATCTCCCGCCTCCTGCAGGAGACCTCCGAGCAGCTGGTGGCGCTGA AGCCCTGGATCACTCGCCAGAACTTCTCCCGGTGCCTGGAGCTGCAGTGTCAGCC CGACTCCTCAACCCTGGGCGGTGGGTCAGGAGGTGGGTCAGGAGGTGGATCCGGA GGTGGCACCCAGGACTGCTCCTTCCAACACAGCCCCATCTCCTCCGACTTCGCTG TCAAAATCCGTGAGCTGTCTGACTACCTGCTTCAAGATTACCCAGTCACCGTGGC CTCCAACCTGCAGGACGAGGAGCTCTGCGGGGGCCTCTGGCGGCTGGTCCTGGCA CAGCGCTGGATGGAGCGGCTCAAGACTGTCGCTGGGTCCAAGATGCAAGGCTTGC TGGAGCGCGTGAACACGGAGATACACTTTGTCACCAAATGTGCCTTTCAGCCCCC CCCCAGCTGTCTTCGCTTCGTCCAG SEQ ID NO;

143.

8. A method of producing a flt3 receptor agonist polypeptide comprising:

growing under suitable nutrient conditions, a host cell transformed or transfected with a replicable vector comprising said nucleic acid molecule of claim 4, 5, 6 or 7 in a manner allowing expression of said flt3 receptor agonist polypeptide and recovering said flt3 receptor agonist polypeptide.

9. A composition comprising;

a polypeptide of claim 1, 2, or 3 and a pharmaceutically acceptable carrier.

10. A composition comprising;

a polypeptide of claim 1, 2, or 3 a factor selected from the group consisting of;

a colony stimulating factor, a cytokine, a lymphokine, an interleukin, and a hematopoietic growth factor; and

a pharmaceutically acceptable carrier.

11. The composition according to claim 10 wherein said factor is selected from the group consisting of:

GM-CSF, G-CSF, c-mpl ligand, M-CSF, IL-1, IL4, IL-2, IL-3, IL-5, IL-6, IL-7, IL-8, L-9, IL-10, IL-11, IL-12, IL-13, IL-15, LIF, flt3 ligand, and EPO.