US2007081979A1PendingUtilityA1
Multi-functional chimeric hematopoietic receptor agonists
Est. expiryOct 25, 2016(expired)· nominal 20-yr term from priority
Inventors:John P. Mc KearnCharles A. McwherterYiqing FengNeena SummersNicholas StatenPhilip StreeterSusan WoulfeNancy I. MinsterJohn C. Minnerly
C07K 2319/00C07K 14/505C07K 14/524C07K 14/535C07K 14/475C07K 14/5403
41
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Claims
Abstract
Disclosed are novel multi-functional chimeric hematopoietic receptor agonist proteins, DNAs which encode the multi-functional chimeric hematopoietic receptor agonist proteins, methods of making the multi-functional chimeric hematopoietic receptor agonist proteins and methods of using the multi-functional chimeric hematopoietic receptor agonist proteins.
Claims
exact text as granted — not AI-modified1 . A hematopoietic protein comprising an amino acid sequence of the formula:
R 1 -L 1 -R 2 , R 2 -L 1 -R 1 , R 1 -R 2 , or R 2 -R 1 wherein R 1 is a human stem cell factor receptor agonist polypeptide, comprising; a modified stem cell factor amino acid sequence of the Formula: SEQ ID NO:465 Glu Gly Ile Cys Arg Asn Arg Val Thr Asn Asn Val 10 Lys Asp Val Thr Lys Leu Val Ala Asn Leu Pro Lys 20 Asp Tyr Met Ile Thr Leu Lys Tyr Val Pro Gly Met 30 Asp Val Leu Pro Ser His Cys Trp Ile Ser Glu Met 40 Val Val Gln Leu Ser Asp Ser Leu Thr Asp Leu Leu 50 60 Asp Lys Phe Ser Asn Ile Ser Glu Gly Leu Ser Asn 70 Tyr Ser Ile Ile Asp Lys Leu Val Asn Ile Val Asp 80 Asp Leu Val Glu Cys Val Lys Glu Asn Ser Ser Lys 90 Asp Leu Lys Lys Ser Phe Lys Ser Pro Glu Pro Arg 100 Leu Phe Thr Pro Glu Glu Phe Phe Arg Ile Phe Asn 110 120 Arg Ser Ile Asp Ala Phe Lys Asp Phe Val Val Ala 130 Ser Glu Thr Ser Asp Cys Val Val Ser Ser Thr Leu 140 Ser Pro Glu Lys Asp Ser Arg Val Ser Val Thr Lys 150 Pro Phe Met Leu Pro Pro Val Ala Ala 160 wherein 1-23 amino acids are optionally deleted from the C-terminus of said stem cell factor receptor agonist polypeptide; and wherein the N-terminus is joined to the C-terminus directly or through a linker (L 2 ) capable of joining the N-terminus to the C-terminus and having new C- and N-termini at amino acids; 23-24 24-25 25-26 26-27 27-28 28-29 29-30 30-31 31-32 32-33 33-34 34-35 35-36 36-37 37-38 38-39 39-40 40-41 64-65 65-66 66-67 67-68 68-69 69-70 70-71 89-90 90-91 91-92 92-93 93-94 94-95 95-96 96-97 97-98 98-99 99-100 100-101 101-102 102-103 103-104 104-105 105-106 106-107 107-108 108-109 109-110 110-111 respectively; R 2 is selected from the group consisting of: a polypeptide comprising; a modified human IL-3 amino acid sequence of the formula: SEQ ID NO:859 Ala Pro Met Thr Gln Thr Thr Ser Leu Lys Thr Ser 1 5 10 Trp Val Asn Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 15 20 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 25 30 35 Xaa Xaa Asn Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 40 45 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 50 55 60 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 65 70 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 75 80 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 85 90 95 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Phe Xaa 100 105 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 110 115 120 Xaa Xaa Xaa Gln Gln Thr Thr Leu Ser Leu Ala Ile 125 130 Phe wherein Xaa at position 17 is Ser, Lys, Gly, Asp, Met, Gln, or Arg; Xaa at position 18 is Asn, His, Leu, Ile, Phe, Arg, or Gln; Xaa at position 19 is Met, Phe, Ile, Arg, Gly, Ala, or Cys; Xaa at position 20 is Ile, Cys, Gln, Glu, Arg, Pro, or Ala; Xaa at position 21 is Asp, Phe, Lys, Arg, Ala, Gly, Glu, Gln, Asn, Thr, Ser or Val; Xaa at position 22 is Glu, Trp, Pro, Ser, Ala, His, Asp, Asn, Gln, Leu, Val or Gly; Xaa at position 23 is Ile, Val, Ala, Gly, Trp, Lys, Phe, Leu, Ser, or Arg; Xaa at position 24 is Ile, Gly, Val, Arg, Ser, Phe, or Leu; Xaa at position 25 is Thr, His, Gly, Gln, Arg, Pro, or Ala; Xaa at position 26 is His, Thr, Phe, Gly, Arg, Ala, or Trp; Xaa at position 27 is Leu, Gly, Arg, Thr, Ser, or Ala; Xaa at position 28 is Lys, Arg, Leu, Gln, Gly, Pro, Val or Trp; Xaa at position 29 is Gln, Asn, Leu, Pro, Arg, or Val; Xaa at position 30 is Pro, His, Thr, Gly, Asp, Gln, Ser, Leu, or Lys; Xaa at position 31 is Pro, Asp, Gly, Ala, Arg, Leu, or Gln; Xaa at position 32 is Leu, Val, Arg, Gln, Asn, Gly, Ala, or Glu; Xaa at position 33 is Pro, Leu, Gln, Ala, Thr, or Glu; Xaa at position 34 is Leu, Val, Gly, Ser, Lys, Glu, Gln, Thr, Arg, Ala, Phe, Ile or Met; Xaa at position 35 is Leu, Ala, Gly, Asn, Pro, Gln, or Val; Xaa at position 36 is Asp, Leu, or Val; Xaa at position 37 is Phe, Ser, Pro, Trp, or Ile; Xaa at position 38 is Asn, or Ala; Xaa at position 40 is Leu, Trp, or Arg; Xaa at position 41 is Asn, Cys, Arg, Leu, His, Met, or Pro; Xaa at position 42 is Gly, Asp, Ser, Cys, Asn, Lys, Thr, Leu, Val, Glu, Phe, Tyr, Ile, Met or Ala; Xaa at position 43 is Glu, Asn, Tyr, Leu, Phe, Asp, Ala, Cys, Gln, Arg, Thr, Gly or Ser; Xaa at position 44 is Asp, Ser, Leu, Arg, Lys, Thr, Met, Trp, Glu, Asn, Gln, Ala or Pro; Xaa at position 45 is Gln, Pro, Phe, Val, Met, Leu, Thr, Lys, Trp, Asp, Asn, Arg, Ser, Ala, Ile, Glu or His; Xaa at position 46 is Asp, Phe, Ser, Thr, Cys, Glu, Asn, Gln, Lys, His, Ala, Tyr, Ile, Val or Gly; Xaa at position 47 is Ile, Gly, Val, Ser, Arg, Pro, or His; Xaa at position 48 is Leu, Ser, Cys, Arg, Ile, His, Phe, Glu, Lys, Thr, Ala, Met, Val or Asn; Xaa at position 49 is Met, Arg, Ala, Gly, Pro, Asn, His, or Asp; Xaa at position 50 is Glu, Leu, Thr, Asp, Tyr, Lys, Asn, Ser, Ala, Ile, Val, His, Phe, Met or Gln; Xaa at position 51 is Asn, Arg, Met, Pro, Ser, Thr, or His; Xaa at position 52 is Asn, His, Arg, Leu, Gly, Ser, or Thr; Xaa at position 53 is Leu, Thr, Ala, Gly, Glu, Pro, Lys, Ser, or Met; Xaa at position 54 is Arg, Asp, Ile, Ser, Val, Thr, Gln, Asn, Lys, His, Ala or Leu; Xaa at position 55 is Arg, Thr, Val, Ser, Leu, or Gly; Xaa at position 56 is Pro, Gly, Cys, Ser, Gin, Glu, Arg, His, Thr, Ala, Tyr, Phe, Leu, Val or Lys; Xaa at position 57 is Asn or Gly; Xaa at position 58 is Leu, Ser, Asp, Arg, Gin, Val, or Cys; Xaa at position 59 is Glu Tyr, His, Leu, Pro, or Arg; Xaa at position 60 is Ala, Ser, Pro, Tyr, Asn, or Thr; Xaa at position 61 is Phe, Asn, Glu, Pro, Lys, Arg, or Ser; Xaa at position 62 is Asn, His, Val, Arg, Pro, Thr, Asp, or Ile; Xaa at position 63 is Arg, Tyr, Trp, Lys, Ser, His, Pro, or Val; Xaa at position 64 is Ala, Asn, Pro, Ser, or Lys; Xaa at position 65 is Val, Thr, Pro, His, Leu, Phe, or Ser; Xaa at position 66 is Lys, Ile, Arg, Val, Asn, Glu, or Ser; Xaa at position 67 is Ser, Ala, Phe, Val, Gly, Asn, Ile, Pro, or His; Xaa at position 68 is Leu, Val, Trp, Ser, Ile, Phe, Thr, or His; Xaa at position 69 is Gln, Ala, Pro, Thr, Glu, Arg, Trp, Gly, or Leu; Xaa at position 70 is Asn, Leu, Val, Trp, Pro, or Ala; Xaa at position 71 is Ala, Met, Leu, Pro, Arg, Glu, Thr, Gln, Trp, or Asn; Xaa at position 72 is Ser, Glu, Met, Ala, His, Asn, Arg, or Asp; Xaa at position 73 is Ala, Glu, Asp, Leu, Ser, Gly, Thr, or Arg; Xaa at position 74 is Ile, Met, Thr, Pro, Arg, Gly, Ala; Xaa at position 75 is Glu, Lys, Gly, Asp, Pro, Trp, Arg, Ser, Gin, or Leu; Xaa at position 76 is Ser, Val, Ala, Asn, Trp, Glu, Pro, Gly, or Asp; Xaa at position 77 is Ile, Ser, Arg, Thr, or Leu; Xaa at position 78 is Leu, Ala, Ser, Glu, Phe, Gly, or Arg; Xaa at position 79 is Lys, Thr, Asn, Met, Arg, Ile, Gly, or Asp; Xaa at position 80 is Asn, Trp, Val, Gly, Thr, Leu, Glu, or Arg; Xaa at position 81 is Leu, Gln, Gly, Ala, Trp, Arg, Val, or Lys; Xaa at position 82 is Leu, Gln, Lys, Trp, Arg, Asp, Glu, Asn, His, Thr, Ser, Ala, Tyr, Phe, Ile, Met or Val; Xaa at position 83 is Pro, Ala, Thr, Trp, Arg, or Met; Xaa at position 84 is Cys, Glu, Gly, Arg, Met, or Val; Xaa at position 85 is Leu, Asn, Val, or Gln; Xaa at position 86 is Pro, Cys, Arg, Ala, or Lys; Xaa at position 87 is Leu, Ser, Trp, or Gly; Xaa at position 88 is Ala, Lys, Arg, Val, or Trp; Xaa at position 89 is Thr, Asp, Cys, Leu, Val, Glu, His, Asn, or Ser; Xaa at position 90 is Ala, Pro, Ser, Thr, Gly, Asp, Ile, or Met; Xaa at position 91 is Ala, Pro, Ser, Thr, Phe, Leu, Asp, or His; Xaa at position 92 is Pro, Phe, Arg, Ser, Lys, His, Ala, Gly, Ile or Leu; Xaa at position 93 is Thr, Asp, Ser, Asn, Pro, Ala, Leu, or Arg; Xaa at position 94 is Arg, Ile, Ser, Glu, Leu, Val, Gln, Lys, His, Ala, or Pro; Xaa at position 95 is His, Gln, Pro, Arg, Val, Leu, Gly, Thr, Asn, Lys, Ser, Ala, Trp, Phe, Ile, or Tyr; Xaa at position 96 is Pro, Lys, Tyr, Gly, Ile, or Thr; Xaa at position 97 is Ile, Val, Lys, Ala, or Asn; Xaa at position 98 is His, Ile, Asn, Leu, Asp, Ala, Thr, Glu, Gln, Ser, Phe, Met, Val, Lys, Arg, Tyr or Pro; Xaa at position 99 is Ile, Leu, Arg, Asp, Val, Pro, Gin, Gly, Ser, Phe, or His; Xaa at position 100 is Lys, Tyr, Leu, His, Arg, Ile, Ser, Gln, or Pro; Xaa at position 101 is Asp, Pro, Met, Lys, His, Thr, Val, Tyr, Glu, Asn, Ser, Ala, Gly, Ile, Leu, or Gln; Xaa at position 102 is Gly, Leu, Glu, Lys, Ser, Tyr, or Pro; Xaa at position 103 is Asp, or Ser; Xaa at position 104 is Trp, Val, Cys, Tyr, Thr, Met, Pro, Leu, Gln, Lys, Ala, Phe, or Gly; Xaa at position 105 is Asn, Pro, Ala, Phe, Ser, Trp, Gln, Tyr, Leu, Lys, Ile, Asp, or His; Xaa at position 106 is Glu, Ser, Ala, Lys, Thr, Ile, Gly, or Pro; Xaa at position 108 is Arg, Lys, Asp, Leu, Thr, Ile, Gln, His, Ser, Ala or Pro; Xaa at position 109 is Arg, Thr, Pro, Glu, Tyr, Leu, Ser, or Gly; Xaa at position 110 is Lys, Ala, Asn, Thr, Leu, Arg, Gln, His, Glu, Ser, or Trp; Xaa at position 111 is Leu, Ile, Arg, Asp, or Met; Xaa at position 112 is Thr, Val, Gln, Tyr, Glu, His, Ser, or Phe; Xaa at position 113 is Phe, Ser, Cys, His, Gly, Trp, Tyr, Asp, Lys, Leu, Ile, Val or Asn; Xaa at position 114 is Tyr, Cys, His, Ser, Trp, Arg, or Leu; Xaa at position 115 is Leu, Asn, Val, Pro, Arg, Ala, His, Thr, Trp, or Met; Xaa at position 116 is Lys, Leu, Pro, Thr, Met, Asp, Val, Glu, Arg, Trp, Ser, Asn, His, Ala, Tyr, Phe, Gln, or Ile; Xaa at position 117 is Thr, Ser, Asn, Ile, Trp, Lys, or Pro; Xaa at position 118 is Leu, Ser, Pro, Ala, Glu, Cys, Asp, or Tyr; Xaa at position 119 is Glu, Ser, Lys, Pro, Leu, Thr, Tyr, or Arg; Xaa at position 120 is Asn, Ala, Pro, Leu, His, Val, or Gln; Xaa at position 121 is Ala, Ser, Ile, Asn, Pro, Lys, Asp, or Gly; Xaa at position 122 is Gln, Ser, Met, Trp, Arg, Phe, Pro, His, Ile, Tyr, or Cys; Xaa at position 123 is Ala, Met, Glu, His, Ser, Pro, Tyr, or Leu; wherein from 1 to 14 amino acids are optionally deleted from the N-terminus and/or from 1 to 15 amino acids are optionally deleted from the C-terminus of said modified human IL-3 amino acid sequence; wherein from 0 to 44 of the amino acids designated by Xaa are different from the corresponding amino acids of native (1-133) human interleukin-3; and wherein the N-terminus is joined to the C-terminus directly or through a linker (L 2 ), capable of joining the N-terminus to the C-terminus and having new C- and N-termini at amino acids; 26-27 27-28 28-29 29-30 30-31 31-32 32-33 33-34 34-35 35-36 36-37 37-38 38-39 39-40 40-41 41-42 49-50 50-51 51-52 52-53 53-54 54-55 64-65 65-66 66-67 67-68 68-69 69-70 70-71 71-72 72-73 82-83 83-84 84-85 85-86 86-87 87-88 88-89 89-90 90-91 91-92 92-93 97-98 98-99 99-100 100-101 101-102 102-103 or 103-104 respectively; a polypeptide comprising; a modified human c-mpl ligand amino acid sequence of the formula: SEQ ID NO:860 Ser Pro Ala Pro Pro Ala Cys Asp Leu Arg Val Leu 1 5 10 Ser Lys Leu Leu Arg Asp Ser His Val Leu His Ser 15 20 Arg Leu Ser Gln Cys Pro Glu Val His Pro Leu Pro 25 30 35 Thr Pro Val Leu Leu Pro Ala Val Asp Phe Ser Leu 40 45 Gly Glu Trp Lys Thr Gln Met Glu Glu Thr Lys Ala 50 55 60 Gln Asp Ile Leu Gly Ala Val Thr Leu Leu Leu Glu 65 70 Gly Val Met Ala Ala Arg Gly Gln Leu Gly Pro Thr 75 80 Cys Leu Ser Ser Leu Leu Gly Gln Leu Ser Gly Gln 85 90 95 Val Arg Leu Leu Leu Gly Ala Leu Gln Ser Leu Leu 100 105 Gly Thr Gln Xaa Xaa Xaa Xaa Gly Arg Thr Thr Ala 110 115 120 His Lys Asp Pro Asn Ala Ile Phe Leu Ser Phe Gln 125 130 His Leu Leu Arg Gly Lys Val Arg Phe Leu Met Leu 135 140 Val Gly Gly Ser Thr Leu Cys Val Arg 145 150 153 wherein: Xaa at position 112 is deleted or Leu, Ala, Val, Ile, Pro, Phe, Trp, or Met; Xaa at position 113 is deleted or Pro, Phe, Ala, Val, Leu, Ile, Trp, or Met; Xaa at position 114 is deleted or Pro, Phe, Ala, Val, Leu, Ile, Trp, or Met; Xaa at position 115 is deleted or Gln, Gly, Ser, Thr, Tyr, or Asn; and wherein the N-terminus is joined to the C-terminus directly or through a linker (L 2 ) capable of joining the N-terminus to the C-terminus and having new C- and N-termini at amino acids; 26-27 27-28 28-29 29-30 30-31 32-33 33-34 34-35 36-37 37-38 38-39 40-41 41-42 42-43 43-44 44-45 46-47 47-48 48-49 50-51 51-52 52-53 53-54 54-55 55-56 56-57 57-58 58-59 59-60 78-79 79-80 80-81 81-82 82-83 83-84 84-85 85-86 86-87 87-88 88-89 108-109 109-110 110-111 111-112 112-113 113-114 114-115 115-116 116-117 117-118 118-119 119-120 120-121 121-122 122-123 123-124 124-125 125-126 126-127 or 127-128 respectively; a colony stimulating factor, a cytokine, a lymphokine, an interleukin, and a hematopoietic growth factor; and wherein L 1 is a linker capable of linking R 1 to R 2 ; said hematopoietic protein can optionally be immediately preceded by (methionine −1 ), (alanine −1 ) or (methionine −2 , alanine −1 ).
2 . A hematopoietic protein comprising; an amino acid sequence of the formula:
R 1 -L 1 -R 2 , R 2 -L 1 -R 1 , R 1 -R 2 , or R 2 -R 1 wherein R 1 is a human stem cell factor receptor agonist polypeptide, comprising; a modified stem cell factor amino acid sequence of the Formula: SEQ ID NO:465 Glu Gly Ile Cys Arg Asn Arg Val Thr Asn Asn Val 10 Lys Asp Val Thr Lys Leu Val Ala Asn Leu Pro Lys 20 Asp Tyr Met Ile Thr Leu Lys Tyr Val Pro Gly Met 30 Asp Val Leu Pro Ser His Cys Trp Ile Ser Glu Met 40 Val Val Gln Leu Ser Asp Ser Leu Thr Asp Leu Leu 50 60 Asp Lys Phe Ser Asn Ile Ser Glu Gly Leu Ser Asn 70 Tyr Ser Ile Ile Asp Lys Leu Val Asn Ile Val Asp 80 Asp Leu Val Glu Cys Val Lys Glu Asn Ser Ser Lys 90 Asp Leu Lys Lys Ser Phe Lys Ser Pro Glu Pro Arg 100 Leu Phe Thr Pro Glu Glu Phe Phe Arg Ile Phe Asn 110 120 Arg Ser Ile Asp Ala Phe Lys Asp Phe Val Val Ala 130 Ser Glu Thr Ser Asp Cys Val Val Ser Ser Thr Leu 140 Ser Pro Glu Lys Asp Ser Arg Val Ser Val Thr Lys 150 Pro Phe Met Leu Pro Pro Val Ala Ala 160 165 wherein 1-23 amino acids are optionally deleted from the C-terminus of said stem cell factor receptor agonist polypeptide; and wherein the N-terminus is joined to the C-terminus directly or through a linker (L 2 ) capable of joining the N-terminus to the C-terminus and having new C- and N-termini at amino acids; 23-24 24-25 25-26 26-27 27-28 28-29 29-30 30-31 31-32 32-33 33-34 34-35 35-36 36-37 37-38 38-39 39-40 40-41 64-65 65-66 66-67 67-68 68-69 69-70 70-71 89-90 90-91 91-92 92-93 93-94 94-95 95-96 96-97 97-98 98-99 99-100 100-101 101-102 102-103 103-104 104-105 105-106 106-107 107-108 108-109 109-110 110-111 respectively; R 2 is selected from the group consisting of: a polypeptide comprising; a modified human IL-3 amino acid sequence of the formula: SEQ ID NO:859 Ala Pro Met Thr Gln Thr Thr Ser Leu Lys Thr Ser 1 5 10 Trp Val Asn Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 15 20 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 25 30 35 Xaa Xaa Asn Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 40 45 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 50 55 60 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 65 70 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 75 80 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 85 90 95 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Phe Xaa 100 105 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 110 115 120 Xaa Xaa Xaa Gln Gln Thr Thr Leu Ser Leu Ala Ile 125 130 Phe wherein Xaa at position 17 is Ser, Lys, Gly, Asp, Met, Gln, or Arg; Xaa at position 18 is Asn, His, Leu, Ile, Phe, Arg, or Gln; Xaa at position 19 is Met, Phe, Ile, Arg, Gly, Ala, or Cys; Xaa at position 20 is Ile, Cys, Gln, Glu, Arg, Pro, or Ala; Xaa at position 21 is Asp, Phe, Lys, Arg, Ala, Gly, Glu, Gin, Asn, Thr, Ser or Val; Xaa at position 22 is Glu, Trp, Pro, Ser, Ala, His, Asp, Asn, Gin, Leu, Val or Gly; Xaa at position 23 is Ile, Val, Ala, Gly, Trp, Lys, Phe, Leu, Ser, or Arg; Xaa at position 24 is Ile, Gly, Val, Arg, Ser, Phe, or Leu; Xaa at position 25 is Thr, His, Gly, Gin, Arg, Pro, or Ala; Xaa at position 26 is His, Thr, Phe, Gly, Arg, Ala, or Trp; Xaa at position 27 is Leu, Gly, Arg, Thr, Ser, or Ala; Xaa at position 28 is Lys, Arg, Leu, Gin, Gly, Pro, Val or Trp; Xaa at position 29 is Gln, Asn, Leu, Pro, Arg, or Val; Xaa at position 30 is Pro, His, Thr, Gly, Asp, Gin, Ser, Leu, or Lys; Xaa at position 31 is Pro, Asp, Gly, Ala, Arg, Leu, or Gin; Xaa at position 32 is Leu, Val, Arg, Gin, Asn, Gly, Ala, or Glu; Xaa at position 33 is Pro, Leu, Gin, Ala, Thr, or Glu; Xaa at position 34 is Leu, Val, Gly, Ser, Lys, Glu, Gin, Thr, Arg, Ala, Phe, Ile or Met; Xaa at position 35 is Leu, Ala, Gly, Asn, Pro, Gin, or Val; Xaa at position 36 is Asp, Leu, or Val; Xaa at position 37 is Phe, Ser, Pro, Trp, or Ile; Xaa at position 38 is Asn, or Ala; Xaa at position 40 is Leu, Trp, or Arg; Xaa at position 41 is Asn, Cys, Arg, Leu, His, Met, or Pro; Xaa at position 42 is Gly, Asp, Ser, Cys, Asn, Lys, Thr, Leu, Val, Glu, Phe, Tyr, Ile, Met or Ala; Xaa at position 43 is Glu, Asn, Tyr, Leu, Phe, Asp, Ala, Cys, Gin, Arg, Thr, Gly or Ser; Xaa at position 44 is Asp, Ser, Leu, Arg, Lys, Thr, Met, Trp, Glu, Asn, Gln, Ala or Pro; Xaa at position 45 is Gin, Pro, Phe, Val, Met, Leu, Thr, Lys, Trp, Asp, Asn, Arg, Ser, Ala, Ile, Glu or His; Xaa at position 46 is Asp, Phe, Ser, Thr, Cys, Glu, Asn, Gin, Lys, His, Ala, Tyr, Ile, Val or Gly; Xaa at position 47 is Ile, Gly, Val, Ser, Arg, Pro, or His; Xaa at position 48 is Leu, Ser, Cys, Arg, Ile, His, Phe, Glu, Lys, Thr, Ala, Met, Val or Asn; Xaa at position 49 is Met, Arg, Ala, Gly, Pro, Asn, His, or Asp; Xaa at position 50 is Glu, Leu, Thr, Asp, Tyr, Lys, Asn, Ser, Ala, Ile, Val, His, Phe, Met or Gin; Xaa at position 51 is Asn, Arg, Met, Pro, Ser, Thr, or His; Xaa at position 52 is Asn, His, Arg, Leu, Gly, Ser, or Thr; Xaa at position 53 is Leu, Thr, Ala, Gly, Glu, Pro, Lys, Ser, or Met; Xaa at position 54 is Arg, Asp, Ile, Ser, Val, Thr, Gin, Asn, Lys, His, Ala or Leu; Xaa at position 55 is Arg, Thr, Val, Ser, Leu, or Gly; Xaa at position 56 is Pro, Gly, Cys, Ser, Gin, Glu, Arg, His, Thr, Ala, Tyr, Phe, Leu, Val or Lys; Xaa at position 57 is Asn or Gly; Xaa at position 58 is Leu, Ser, Asp, Arg, Gin, Val, or Cys; Xaa at position 59 is Glu Tyr, His, Leu, Pro, or Arg; Xaa at position 60 is Ala, Ser, Pro, Tyr, Asn, or Thr; Xaa at position 61 is Phe, Asn, Glu, Pro, Lys, Arg, or Ser; Xaa at position 62 is Asn, His, Val, Arg, Pro, Thr, Asp, or Ile; Xaa at position 63 is Arg, Tyr, Trp, Lys, Ser, His, Pro, or Val; Xaa at position 64 is Ala, Asn, Pro, Ser, or Lys; Xaa at position 65 is Val, Thr, Pro, His, Leu, Phe, or Ser; Xaa at position 66 is Lys, Ile, Arg, Val, Asn, Glu, or Ser; Xaa at position 67 is Ser, Ala, Phe, Val, Gly, Asn, Ile, Pro, or His; Xaa at position 68 is Leu, Val, Trp, Ser, Ile, Phe, Thr, or His; Xaa at position 69 is Gln, Ala, Pro, Thr, Glu, Arg, Trp, Gly, or Leu; Xaa at position 70 is Asn, Leu, Val, Trp, Pro, or Ala; Xaa at position 71 is Ala, Met, Leu, Pro, Arg, Glu, Thr, Gln, Trp, or Asn; Xaa at position 72 is Ser, Glu, Met, Ala, His, Asn, Arg, or Asp; Xaa at position 73 is Ala, Glu, Asp, Leu, Ser, Gly, Thr, or Arg; Xaa at position 74 is Ile, Met, Thr, Pro, Arg, Gly, Ala; Xaa at position 75 is Glu, Lys, Gly, Asp, Pro, Trp, Arg, Ser, Gln, or Leu; Xaa at position 76 is Ser, Val, Ala, Asn, Trp, Glu, Pro, Gly, or Asp; Xaa at position 77 is Ile, Ser, Arg, Thr, or Leu; Xaa at position 78 is Leu, Ala, Ser, Glu, Phe, Gly, or Arg; Xaa at position 79 is Lys, Thr, Asn, Met, Arg, Ile, Gly, or Asp; Xaa at position 80 is Asn, Trp, Val, Gly, Thr, Leu, Glu, or Arg; Xaa at position 81 is Leu, Gln, Gly, Ala, Trp, Arg, Val, or Lys; Xaa at position 82 is Leu, Gln, Lys, Trp, Arg, Asp, Glu, Asn, His, Thr, Ser, Ala, Tyr, Phe, Ile, Met or Val; Xaa at position 83 is Pro, Ala, Thr, Trp, Arg, or Met; Xaa at position 84 is Cys, Glu, Gly, Arg, Met, or Val; Xaa at position 85 is Leu, Asn, Val, or Gln; Xaa at position 86 is Pro, Cys, Arg, Ala, or Lys; Xaa at position 87 is Leu, Ser, Trp, or Gly; Xaa at position 88 is Ala, Lys, Arg, Val, or Trp; Xaa at position 89 is Thr, Asp, Cys, Leu, Val, Glu, His, Asn, or Ser; Xaa at position 90 is Ala, Pro, Ser, Thr, Gly, Asp, Ile, or Met; Xaa at position 91 is Ala, Pro, Ser, Thr, Phe, Leu, Asp, or His; Xaa at position 92 is Pro, Phe, Arg, Ser, Lys, His, Ala, Gly, Ile or Leu; Xaa at position 93 is Thr, Asp, Ser, Asn, Pro, Ala, Leu, or Arg; Xaa at position 94 is Arg, Ile, Ser, Glu, Leu, Val, Gln, Lys, His, Ala, or Pro; Xaa at position 95 is His, Gln, Pro, Arg, Val, Leu, Gly, Thr, Asn, Lys, Ser, Ala, Trp, Phe, Ile, or Tyr; Xaa at position 96 is Pro, Lys, Tyr, Gly, Ile, or Thr; Xaa at position 97 is Ile, Val, Lys, Ala, or Asn; Xaa at position 98 is His, Ile, Asn, Leu, Asp, Ala, Thr, Glu, Gln, Ser, Phe, Met, Val, Lys, Arg, Tyr or Pro; Xaa at position 99 is Ile, Leu, Arg, Asp, Val, Pro, Gln, Gly, Ser, Phe, or His; Xaa at position 100 is Lys, Tyr, Leu, His, Arg, Ile, Ser, Gln, or Pro; Xaa at position 101 is Asp, Pro, Met, Lys, His, Thr, Val, Tyr, Glu, Asn, Ser, Ala, Gly, Ile, Leu, or Gln; Xaa at position 102 is Gly, Leu, Glu, Lys, Ser, Tyr, or Pro; Xaa at position 103 is Asp, or Ser; Xaa at position 104 is Trp, Val, Cys, Tyr, Thr, Met, Pro, Leu, Gln, Lys, Ala, Phe, or Gly; Xaa at position 105 is Asn, Pro, Ala, Phe, Ser, Trp, Gln, Tyr, Leu, Lys, Ile, Asp, or His; Xaa at position 106 is Glu, Ser, Ala, Lys, Thr, Ile, Gly, or Pro; Xaa at position 108 is Arg, Lys, Asp, Leu, Thr, Ile, Gln, His, Ser, Ala or Pro; Xaa at position 109 is Arg, Thr, Pro, Glu, Tyr, Leu, Ser, or Gly; Xaa at position 110 is Lys, Ala, Asn, Thr, Leu, Arg, Gln, His, Glu, Ser, or Trp; Xaa at position 111 is Leu, Ile, Arg, Asp, or Met; Xaa at position 112 is Thr, Val, Gln, Tyr, Glu, His, Ser, or Phe; Xaa at position 113 is Phe, Ser, Cys, His, Gly, Trp, Tyr, Asp, Lys, Leu, Ile, Val or Asn; Xaa at position 114 is Tyr, Cys, His, Ser, Trp, Arg, or Leu; Xaa at position 115 is Leu, Asn, Val, Pro, Arg, Ala, His, Thr, Trp, or Met; Xaa at position 116 is Lys, Leu, Pro, Thr, Met, Asp, Val, Glu, Arg, Trp, Ser, Asn, His, Ala, Tyr, Phe, Gln, or Ile; Xaa at position 117 is Thr, Ser, Asn, Ile, Trp, Lys, or Pro; Xaa at position 118 is Leu, Ser, Pro, Ala, Glu, Cys, Asp, or Tyr; Xaa at position 119 is Glu, Ser, Lys, Pro, Leu, Thr, Tyr, or Arg; Xaa at position 120 is Asn, Ala, Pro, Leu, His, Val, or Gln; Xaa at position 121 is Ala, Ser, Ile, Asn, Pro, Lys, Asp, or Gly; Xaa at position 122 is Gln, Ser, Met, Trp, Arg, Phe, Pro, His, Ile, Tyr, or Cys; Xaa at position 123 is Ala, Met, Glu, His, Ser, Pro, Tyr, or Leu; wherein from 1 to 14 amino acids are optionally deleted from the N-terminus and/or from 1 to 15 amino acids are optionally deleted from the C-terminus of said modified human IL-3 amino acid sequence; wherein from 0 to 44 of the amino acids designated by Xaa are different from the corresponding amino acids of native (1-133) human interleukin-3; and wherein the N-terminus is joined to the C-terminus directly or through a linker (L 2 ), capable of joining the N-terminus to the C-terminus and having new C- and N-termini at amino acids; 26-27 27-28 28-29 29-30 30-31 31-32 32-33 33-34 34-35 35-36 36-37 37-38 38-39 39-40 40-41 41-42 49-50 50-51 51-52 52-53 53-54 54-55 64-65 65-66 66-67 67-68 68-69 69-70 70-71 71-72 72-73 82-83 83-84 84-85 85-86 86-87 87-88 88-89 89-90 90-91 91-92 92-93 97-98 98-99 99-100 100-101 101-102 102-103 or 103-104 respectively; and wherein L 1 is a linker capable of linking R 1 to R 2 ; said hematopoietic protein can optionally be immediately preceded by (methionine −1 ), (alanine −1 ) or (methionine −2 , alanine −1 ).
3 . The hematopoeitic protein of claim 2 wherein R 2 is selected from the group consisting of:
SEQ ID NO:803
Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His
His Leu Lys Arg Pro Pro Ala Pro Leu Leu Asp Pro
Asn Asn Leu Asn Ala Glu Asp Val Asp Ile Leu Met
Glu Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe
Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly
Ile Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu
Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile
Ile Ile Lys Ala Gly Asp Trp Gln Glu Phe Arg Glu
Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gln Ala
Gln Glu Gln Gln;
SEQ ID NO:804
Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His
His Leu Lys Arg Pro Pro Asn Pro Leu Leu Asp Pro
Asn Asn Leu Asn Ser Glu Asp Met Asp Ile Leu Met
Glu Arg Asn Leu Arg Thr Pro Asn Leu Leu Ala Phe
Val Arg Ala Val Lys His Leu Glu Asn Ala Ser Gly
Ile Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu
Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile
Ile Ile Lys Ala Gly Asp Trp Gln Glu Phe Arg Glu
Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gln Ala
Gln Glu Gln Gln;
SEQ ID NO:805
Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His
His Leu Lys Val Pro Pro Ala Pro Leu Leu Asp Ser
Asn Asn Leu Asn Ser Glu Asp Met Asp Ile Leu Met
Glu Arg Asn Leu Arg Leu Pro Asn Leu Leu Ala Phe
Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly
Ile Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu
Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile
Ile Ile Lys Ala Gly Asp Trp Gln Glu Phe Arg Glu
Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gln Ala
Gln Glu Gln Gln;
and
SEQ ID NO:806
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His
Leu Lys Arg Pro Pro Ala Pro Leu Leu Asp Pro Asn
Asn Leu Asn Asp Glu Asp Val Ser Ile Leu Met Asp
Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val
Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro
Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Ile
Ile Lys Ala Gly Asp Trp Gln Glu Phe Arg Glu Lys
Leu Thr Phe Tyr Leu Val Thr Leu Glu Gln Ala Gln
Glu Gln Gln.
4 . A hematopoietic protein comprising; an amino acid sequence of the formula:
R 1 -L 1 -R 2 , R 2 -L 1 -R 1 , R 1 -R 2 , or R 2 -R 1 wherein R 1 is a human stem cell factor receptor agonist polypeptide, comprising; a modified stem cell factor amino acid sequence of the Formula: SEQ ID NO:465 Glu Gly Ile Cys Arg Asr Arg Val Thr Asn Asn Val 10 Lys Asp Val Thr Lys Leu Val Ala Asn Leu Pro Lys 20 Asp Tyr Met Ile Thr Leu Lys Tyr Val Pro Gly Met 30 Asp Val Leu Pro Ser His Cys Trp Ile Ser Glu Met 40 Val Val Gln Leu Ser Asp Ser Leu Thr Asp Leu Leu 50 60 Asp Lys Phe Ser Asn Ile Ser Glu Gly Leu Ser Asn 70 Tyr Ser Ile Ile Asp Lys Leu Val Asn Ile Val Asp 80 Asp Leu Val Glu Cys Val Lys Glu Asn Ser Ser Lys 90 Asp Leu Lys Lys Ser Phe Lys Ser Pro Glu Pro Arg 100 Leu Phe Thr Pro Glu Glu Phe Phe Arg Ile Phe Asn 110 120 Arg Ser Ile Asp Ala Phe Lys Asp Phe Val Val Ala 130 Ser Glu Thr Ser Asp Cys Val Val Ser Ser Thr Leu 140 Ser Pro Glu Lys Asp Ser Arg Val Ser Val Thr Lys 150 Pro Phe Met Leu Pro Pro Val Ala Ala 160 165 wherein 1-23 amino acids are optionally deleted from the C-terminus of said stem cell factor receptor agonist polypeptide; and wherein the N-terminus is joined to the C-terminus directly or through a linker (L 2 ) capable of joining the N-terminus to the C-terminus and having new C- and N-termini at amino acids; 23-24 24-25 25-26 26-27 27-28 28-29 29-30 30-31 31-32 32-33 33-34 34-35 35-36 36-37 37-38 38-39 39-40 40-41 64-65 65-66 66-67 67-68 68-69 69-70 70-71 89-90 90-91 91-92 92-93 93-94 94-95 95-96 96-97 97-98 98-99 99-100 100-101 101-102 102-103 103-104 104-105 105-106 106-107 107-108 108-109 109-110 110-111 respectively; R 2 is selected from the group consisting of: a polypeptide comprising; a modified human c-mpl ligand amino acid sequence of the formula: SEQ ID NO:860 Ser Pro Ala Pro Pro Ala Cys Asp Leu Arg Val Leu 1 5 10 Ser Lys Leu Leu Arg Asp Ser His Val Leu His Ser 15 20 Arg Leu Ser Gln Cys Pro Glu Val His Pro Leu Pro 25 30 35 Thr Pro Val Leu Leu Pro Ala Val Asp Phe Ser Leu 40 45 Gly Glu Trp Lys Thr Gln Met Glu Glu Thr Lys Ala 50 55 60 Gln Asp Ile Leu Gly Ala Val Thr Leu Leu Leu Glu 65 70 Gly Val Met Ala Ala Arg Gly Gln Leu Gly Pro Thr 75 80 Cys Leu Ser Ser Leu Leu Gly Gln Leu Ser Gly Gln 85 90 95 Val Arg Leu Leu Leu Gly Ala Leu Gln Ser Leu Leu 100 105 Gly Thr Gln Xaa Xaa Xaa Xaa Gly Arg Thr Thr Ala 110 120 His Lys Asp Pro Asn Ala Ile Phe Leu Ser Phe Gln 125 130 His Leu Leu Arg Gly Lys Val Arg Phe Leu Met Leu 135 140 Val Gly Gly Ser Thr Leu Cys Val Arg 145 150 153 wherein; Xaa at position 112 is deleted or Leu, Ala, Val, Ile, Pro, Phe, Trp, or Met; Xaa at position 113 is deleted or Pro, Phe, Ala, Val, Leu, Ile, Trp, or Met; Xaa at position 114 is deleted or Pro, Phe, Ala, Val, Leu, Ile, Trp, or Met; Xaa at position 115 is deleted or Gln, Gly, Ser, Thr, Tyr, or Asn; and wherein the N-terminus is joined to the C-terminus directly or through a linker (L 2 ) capable of joining the N-terminus to the C-terminus and having new C- and N-termini at amino acids; 26-27 27-28 28-29 29-30 30-31 32-33 33-34 34-35 36-37 37-38 38-39 40-41 41-42 42-43 43-44 44-45 46-47 47-48 48-49 50-51 51-52 52-53 53-54 54-55 55-56 56-57 57-58 58-59 59-60 78-79 79-80 80-81 81-82 82-83 83-84 84-85 85-86 86-87 87-88 88-89 108-109 109-110 110-111 111-112 112-113 113-114 114-115 115-116 116-117 117-118 118-119 119-120 120-121 121-122 122-123 123-124 124-125 125-126 126-127 or 127-128 respectively; and wherein L 1 is a linker capable of linking R 1 to R 2 ; said hematopoietic protein can optionally be immediately preceded by (methionine −1 ), (alanine −1 ) or (methionine −2 , alanine −1 ).
5 . A hematopoietic protein comprising; an amino acid sequence of the formula:
R 1 -L 1 -R 2 , R 2 -L 1 -R 1 , R 1 -R 2 , or R 2 -R 1 wherein R 1 is a human stem cell factor receptor agonist polypeptide, comprising; a modified stem cell factor amino acid sequence of the Formula: SEQ ID NO:465 Glu Gly Ile Cys Arg Asn Arg Val Thr Asn Asn Val 10 Lys Asp Val Thr Lys Leu Val Ala Asn Leu Pro Lys 20 Asp Tyr Met Ile Thr Leu Lys Tyr Val Pro Gly Met 30 Asp Val Leu Pro Ser His Cys Trp Ile Ser Glu Met 40 Val Val Gln Leu Ser Asp Ser Leu Thr Asp Leu Leu 50 60 Asp Lys Phe Ser Asn Ile Ser Glu Gly Leu Ser Asn 70 Tyr Ser Ile Ile Asp Lys Leu Val Asn Ile Val Asp 80 Asp Leu Val Glu Cys Val Lys Glu Asn Ser Ser Lys 90 Asp Leu Lys Lys Ser Phe Lys Ser Pro Glu Pro Arg 100 Leu Phe Thr Pro Glu Glu Phe Phe Arg Ile Phe Asn 110 120 Arg Ser Ile Asp Ala Phe Lys Asp Phe Val Val Ala 130 Ser Glu Thr Ser Asp Cys Val Val Ser Ser Thr Leu 140 Ser Pro Glu Lys Asp Ser Arg Val Ser Val Thr Lys 150 Pro Phe Met Leu Pro Pro Val Ala Ala 160 165 wherein 1-23 amino acids are optionally deleted from the C-terminus of said stem cell factor receptor agonist polypeptide; and wherein the N-terminus is joined to the C-terminus directly or through a linker (L 2 ) capable of joining the N-terminus to the C-terminus and having new C- and N-termini at amino acids; 23-24 24-25 25-26 26-27 27-28 28-29 29-30 30-31 31-32 32-33 33-34 34-35 35-36 36-37 37-38 38-39 39-40 40-41 64-65 65-66 66-67 67-68 68-69 69-70 70-71 89-90 90-91 91-92 92-93 93-94 94-95 95-96 96-97 97-98 98-99 99-100 100-101 101-102 102-103 103-104 104-105 105-106 106-107 107-108 108-109 109-110 110-111 respectively; R 2 is selected from the group consisting of: a colony stimulating factor, a cytokine, a lymphokine, an interleukin, and a hematopoietic growth factor; and wherein L 1 is a linker capable of linking R 1 to R 2 ; said hematopoietic protein can optionally be immediately preceded by (methionine −1 ), (alanine −1 ) or (methionine −2 , alanine −1 ).
6 . The hematopoietic protein as recited in claim 1 , 2 , 3 , 4 or 5 wherein said linker (L 2 ) is selected from the group consisting of:
Ser;
Asn;
Gly;
Thr;
Gly Ser;
Ala Ala;
Gly Ser Gly;
Gly Gly Gly;
Gly Asn Gly;
Gly Ala Gly;
Gly Thr Gly;
Ala Ser Ala;
Ala Ala Ala;
SEQ ID NO:778
Gly Gly Gly Ser;
SEQ ID NO:779
Gly Gly Gly Ser Gly Gly Gly Ser;
SEQ ID NO:780
Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser;
SEQ ID NO:781
Ser Gly Gly Ser Gly Gly Ser;
SEQ ID NO:782
Glu Phe Gly Asn Met;
SEQ ID NO:783
Glu Phe Gly Gly Asn Met;
SEQ ID NO:784
Glu Phe Gly Gly Asn Gly Gly Asn Met;
SEQ ID NO:785
Gly Gly Ser Asp Met Ala Gly;
SEQ ID NO:786
Ser Gly Gly Asn Gly;
SEQ ID NO:787
Ser Gly Gly Asn Gly Ser Gly Gly Asn Gly;
SEQ ID NO:788
Ser Gly Gly Asn Gly Ser Gly Gly Asn Gly Ser Gly
Gly Asn Gly;
SEQ ID NO:789
Ser Gly Gly Ser Gly Ser Gly Gly Ser Gly;
SEQ ID NO:790
Ser Gly Gly Ser Gly Ser Gly Gly Ser Gly Ser Gly
Gly Ser Gly;
SEQ ID NO:791
Gly Gly Gly Ser Gly Gly;
SEQ ID NO:792
Gly Gly Gly Ser Gly Gly Gly;
SEQ ID NO:793
Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly
SEQ ID NO:794
Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser
Gly;
SEQ ID NO:795
Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser
Gly Gly Gly;
SEQ ID NO:796
Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser
Gly Gly Gly Ser Gly Gly Gly Ser Gly;
SEQ ID NO:797
Pro Pro Pro Trp Ser Pro Arg Pro Leu Gly Ala Thr
Ala Pro Thr Ala Gly Gln Pro Pro Leu;
SEQ ID NO:798
Pro Pro Pro Trp Ser Pro Arg Pro Leu Gly Ala Thr
Ala Pro Thr;
and
SEQ ID NO:799
Val Glu Thr Val Phe His Arg Val Ser Gln Asp Gly
Leu Leu Thr Ser.
7 . The hematopoietic protein of claim 1 or 5 , wherein said colony stimulating factor is selected from the group consisting of GM-CSF, G-CSF, G-CSF Ser 17 , c-mpl ligand (TPO), M-CSF, erythropoietin (EPO), IL-1, IL-4, IL-2, IL-3, IL-5, IL 6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, LIF, flt3/flk2 ligand, human growth hormone, B-cell growth factor, B-cell differentiation factor, eosinophil differentiation factor and stem cell factor (SCF).
8 . The hematopoietic protein of claim 7 wherein said colony stimulating factor is selected from the group consisting of G-CSF, G-CSF Ser 17 , G-CSF Ala 17 and c-mpl ligand (TPO).
9 . A nucleic acid molecule encoding said hematopoietic protein of claim 1 .
10 . A nucleic acid molecule encoding said hematopoietic protein of claim 2 .
11 . A nucleic acid molecule encoding said hematopoietic protein of claim 3 .
12 . A nucleic acid molecule encoding said hematopoietic protein of claim 4 .
13 . A nucleic acid molecule encoding said hematopoietic protein of claim 5 .
14 . A nucleic acid molecule encoding said hematopoietic protein of claim 6 .
15 . A nucleic acid molecule encoding said hematopoietic protein of claim 7 .
16 . A nucleic acid molecule encoding said hematopoietic protein of claim 8 .
17 . A method of producing a hematopoietic protein comprising: growing under suitable nutrient conditions, a host cell transformed or transfected with a replicable vector comprising a nucleic acid molecule of claim 9 , 10 , 11 , 12 , 13 , 14 , 15 or 16 in a manner allowing expression of said hematopoietic protein and recovering said hematopoietic protein.
18 . A pharmaceutical composition comprising; the hematopoietic protein according to claim 1 , 2 , 3 , 4 or 5 ; and a pharmaceutically acceptable carrier.
19 . A method of stimulating the production of hematopoietic cells in a patient comprising the step of administering an effective amount of the hematopoietic protein as recited in claim 1 , 2 , 3 , 4 or 5 to said patient.
20 . A method for selective ex vivo expansion of hematopoietic cells, comprising the steps of;
(a) culturing said hematopoietic cells in a culture medium comprising; the hematopoietic protein of claim 1; and (b) harvesting said cultured cells.
21 . A method for selective ex vivo expansion of hematopoietic cells, comprising the steps of:
(a) separating hematopoietic cells from other cells; (b) culturing said separated hematopoietic cells in a culture medium comprising; the hematopoietic protein of claim 1; and (c) harvesting said cultured cells.
22 . A method for treatment of a patient having a hematopoietic disorder, comprising the steps of:
(a) removing hematopoietic cells from said patient; (b) culturing said hematopoietic cells in a culture medium comprising; the hematopoietic protein of claim 1; (c) harvesting said cultured cells; and (d) transplanting said cultured cells into said patient.
23 . A method for treatment of a patient having a hematopoietic disorder, comprising the steps of:
(a) removing hematopoietic cells from said patient; (b) separating hematopoietic cells from other cells; (c) culturing said separated hematopoietic cells in a culture medium comprising; the hematopoietic protein of claim 1; (d) harvesting said cultured cells; and (e) transplanting said cultured cells into said patient.
24 . A method of human gene therapy, comprising the steps of:
(a) removing hematopoietic cells from a patient; (b) separating said hematopoietic cells from other cells; (c) culturing said separated hematopoietic cells in a culture medium comprising; the hematopoietic protein of claim 1; (d) introducing DNA into said cultured cells; (e) harvesting said transduced cells; and (f) transplanting said transduced cells into said patient.
25 . The method according to claim 20 , 21 , 22 , 23 or 24 wherein said hematopoietic cells are CD34+ cells.
26 . The method according to claim 20 , 21 , 22 , 23 or 24 wherein said hematopoietic cells are peripheral blood cells.
27 . A method for the production of dendritic cells comprising the steps of:
a) separating hematopoietic progenitor cells or CD34+ cells from other cells; and b) culturing said hematopoietic progenitor cells or CD34+ cells in a growth medium, comprising the hematopoietic protein of claim 1 , 2 , 3 , 4 or 5 .
28 . The method of claim 27 , further comprising the step of pulsing said culturing hematopoietic progenitor cells or CD34+ cells with an antigen.
29 . The method of claim 27 , wherein said growth medium, further comprises one or more factor selected from the group consisting of; GM-CSF, IL-4, TNF-α, stem cell factor (SCF), flt-3 ligand, IL-3, an IL-3 variant, an IL-3 variant fusion protein, and a multi-functional receptor agonist.
30 . The method of claim 28 , wherein said growth medium, further comprises one or more factor selected from the group consisting of; GM-CSF, IL-4, TNF-α, stem cell factor (SCF), flt-3 ligand, IL-3, an IL-3 variant, an IL-3 variant fusion protein, and a multi-functional receptor agonist.
31 . A method for treating a human having a tumor, infection or auto-immune disease, comprising the step of; administering the hematopoietic protein of claim 1 , 2 , 3 , 4 or 5 to said human.
32 . The method of claim 31 , further comprising administrating one or more factor selected from the group consisting of; GM-CSF, IL-4, TNF-α, stem cell factor (SCF), flt-3 ligand, IL-3, an IL-3 variant, an IL-3 variant fusion protein, and a multi-functional receptor agonist.
33 . The method of claim 31 , further comprising the step of administering an antigen to said patient.
34 . The method of claim 32 , further comprising the step of administering an antigen to said patient.
35 . A method for treating a human having a tumor, infection or auto-immune disease, comprising the step of:
a) mobilizing dendritic cell progenitors or mature dendritic cells by administering the hematopoietic protein of claim 1 to said human; b) removing said dendritic cell precursors or mature dendritic cells by a blood draw or pheresis; c) pulsing said dendritic cell precursors or mature dendritic cells with an antigen; and d) returning said antigen pulsed dendritic cell precursors or mature dendritic cells to said human.
36 . The method of claim 35 , further comprising administering in step a), one or more factor selected from the group consisting of; GM-CSF, IL-4, TNF-α, stem cell factor (SCF), flt-3 ligand, IL-3, an IL-3 variant, an IL-3 variant fusion protein, and a multi-functional receptor agonist.
37 . The method of claim 35 , further comprising the step of culturing said dendritic cell precursors or mature dendritic cells from step b), in a growth medium, comprising; the hematopoietic protein of claim 1 , 2 , 3 or 4 .
38 . The method of claim 36 , further comprising the step of culturing said dendritic cell precursors or mature dendritic cells from step b), in a growth medium, comprising; the hematopoietic protein of claim 1 , 2 , 3 , 4 or 5 .
39 . The method of claim 37 , wherein said growth medium, further comprises one or more factor selected from the group consisting of; GM-CSF, IL-4, TNF-α, stem cell factor (SCF), flt-3 ligand, IL-3, an IL-3 variant, an IL-3 variant fusion protein, and a multi-functional receptor agonist.
40 . The method of claim 38 , wherein said growth medium, further comprises one or more factor selected from the group consisting of; GM-CSF, IL-4, TNF-α, stem cell factor (SCF), flt-3 ligand, IL-3, an IL-3 variant, an IL-3 variant fusion protein, and a multi-functional receptor agonist.
41 . A method for treating a human having a tumor, infection or auto-immune disease, comprising the steps of:
a) removing hematopoietic progenitor cells or CD34+cells from said human by a blood draw or pheresis; b) culturing said hematopoietic progenitor cells or CD34+ cells in a growth medium, comprising the hematopoietic protein of claim 1 to produce dendritic cell precursors or mature dendritic cells; and c) returning said dendritic cell precursors or mature dendritic cells to said human.
42 . A method for treating a human having a tumor, infection or auto-immune disease, comprising the steps of:
a) removing hematopoietic progenitor cells or CD34+cells from said patient by a blood draw or pheresis; b) culturing said hematopoietic progenitor cells or CD34+ cells in a growth medium, comprising the hematopoietic protein of claim 1 to produce dendritic cell precursors or mature dendritic cells; c) pulsing said dendritic cell precursors or mature dendritic cells with an antigen; and d) returning said antigen pulsed dendritic cell precursors or mature dendritic cells to said human.
43 . The method of claim 41 , further comprising the step of separating said hematopoietic progenitor cells or CD34+cells from other cells prior to culturing.
44 . The method of claim 42 , further comprising the step of separating said hematopoietic progenitor cells or CD34+cells from other cells prior to culturing.
45 . The method of claim 42 , wherein said culture medium further comprises one or more factor selected from the group consisting of: GM-CSF, IL-4, TNF-α, stem cell factor (SCF), flt-3 ligand, IL-3, an IL-3 variant, an IL-3 variant fusion protein, and a multi-functional receptor agonist.
46 . The method of claim 43 , wherein said culture medium further comprises one or more factor selected from the group consisting of: GM-CSF, IL-4, TNF-α, stem cell factor (SCF), flt-3 ligand, IL-3, an IL-3 variant, an IL-3 variant fusion protein, and a multi-functional receptor agonist.
47 . The method of claim 44 , wherein said culture medium further comprises one or more factor selected from the group consisting of: GM-CSF, IL-4, TNF-α, stem cell factor (SCF), flt-3 ligand, IL-3, an IL-3 variant, an IL-3 variant fusion protein, and a multi-functional receptor agonist.Cited by (0)
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