Circular permuteins of flt3 ligand

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.

We claim the following:  
     
         1 . A method of stimulating the production of hematopoietic cells in a patient comprising the step of administering a polypeptide to the patient wherein the polypeptide is a human flt-3 receptor agonist polypeptide comprising a modified flt-3 ligand amino acid sequence selected from the group consisting of: 
 (i) the sequence of SEQ ID NO: 144; and    (ii) a polypeptide comprising residues 1-132 of SEQ ID NO:144;    wherein the modification comprises the linear rearrangement of the sequences of (i) or (ii); 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, 87-88, 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 the flt-3 receptor agonist polypeptide is immediately preceded by (methionine −1 ), (alanine −1 ) or (methionine −2 , alanine −1 ).    
     
     
         2 . A method of stimulating the production of hematopoietic cells in a patient comprising the step of administering a composition to the patient wherein the composition comprises a pharmaceutically acceptable carrier and a human flt-3 receptor agonist polypeptide comprising a modified flt-3 ligand amino acid sequence selected from the group consisting of: 
 (i) the sequence of SEQ ID NO: 144; and    (ii) a polypeptide comprising residues 1-132 of SEQ ID NO:144;    wherein the modification comprises the linear rearrangement of the sequences of (i) or (ii); 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, 87-88, 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 the flt-3 receptor agonist polypeptide is immediately preceded by (methionine −1 ), (alanine −1 ) or (methionine −2 , alanine −1 ).    
     
     
         3 . A method for selective ex vivo expansion of stem cells comprising the steps of: 
 (a) separating hematopoietic cells from other cells;    (b) culturing the separated hematopoietic cells in a culture medium comprising a human flt-3 receptor agonist polypeptide comprising a modified flt-3 ligand amino acid sequence selected from the group consisting of:    (i) the sequence of SEQ ID NO: 144; and    (ii) a polypeptide comprising residues 1-132 of SEQ ID NO:144;    wherein the modification comprises the linear rearrangement of the sequences of (i) or (ii); 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, 87-88, 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 the flt-3 receptor agonist polypeptide is immediately preceded by (methionine −1 ), (alanine −1 ) or (methionine −2 , alanine −1 ); and    (c) harvesting the cultured cells.    
     
     
         4 . A method for selective ex vivo expansion of hematopoietic cells comprising the steps of: 
 (a) culturing the hematopoietic cells in a culture medium comprising a composition including a pharmaceutically acceptable carrier and a human flt-3 receptor agonist polypeptide comprising a modified flt-3 ligand amino acid sequence selected from the group consisting of:    (i) the sequence of SEQ ID NO: 144; and    (ii) a polypeptide comprising the residues 1-132 of SEQ ID NO:144;    wherein the modification comprises the linear rearrangement of the sequences of (i) or (ii); 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, 87-88, 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 the flt-3 receptor agonist polypeptide is immediately preceded by (methionine −1 ), (alanine −1 ) or (methionine −2 , alanine −1 ); and    (b) harvesting the cultured cells.    
     
     
         5 . A method for selective ex vivo expansion of hematopoietic cells comprising the steps of: 
 (a) separating hematopoietic cells from other cells;    (b) culturing the separated hematopoietic cells in a culture medium comprising a composition including a pharmaceutically acceptable carrier and a human flt-3 receptor agonist polypeptide comprising a modified flt-3 ligand amino acid sequence selected from the group consisting of:    (i) the sequence of SEQ ID NO: 144; and    (ii) a polypeptide comprising residues 1-132 of SEQ ID NO:144;    wherein the modification comprises the linear rearrangement of the sequences of (i) or (ii); 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, 87-88, 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 the flt-3 receptor agonist polypeptide is immediately preceded by (methionine −1 ), (alanine −1 ) or (methionine −2 , alanine −1 ); and    (c) harvesting the cultured cells.    
     
     
         6 . A method for treatment of a patient having a hematopoietic disorder comprising the steps of: 
 (a) removing hematopoietic cells from the patient;    (b) culturing the separated hematopoietic cells in a culture medium comprising a human flt-3 receptor agonist polypeptide comprising a modified flt-3 ligand amino acid sequence selected from the group consisting of:    (i) the sequence of SEQ ID NO: 144; and    (ii) a polypeptide comprising residues 1-132 of SEQ ID NO:144;    wherein the modification comprises the linear rearrangement of the sequences of (i) or (ii); 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, 87-88, 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 the flt-3 receptor agonist polypeptide is immediately preceded by (methionine −1 ), (alanine −1 ) or (methionine −2 , alanine −1 );    (c) harvesting the cultured cells; and    (d) transplanting the cultured cells into the patient.    
     
     
         7 . A method for treatment of a patient having a hematopoietic disorder comprising the steps of: 
 (a) removing hematopoietic cells from the patient;    (b) separating the hematopoietic cells from other cells;    (c) culturing the separated hematopoietic cells in a culture medium comprising a human flt-3 receptor agonist polypeptide comprising a modified flt-3 ligand amino acid sequence selected from the group consisting of:    (i) the sequence of SEQ ID NO: 144; and    (ii) a polypeptide comprising residues 1-132 of SEQ ID NO:144;    wherein the modification comprises the linear rearrangement of the sequences of (i) or (ii); 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, 87-88, 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 the flt-3 receptor agonist polypeptide is immediately preceded by (methionine −1 ), (alanine −1 ) or (methionine −2 , alanine −1 );    (d) harvesting the cultured cells; and    (e) transplanting the cultured cells into the patient.    
     
     
         8 . A method for treatment of a patient having a hematopoietic disorder, comprising the steps of: 
 (a) removing hematopoietic cells from the patient;    (b) culturing the hematopoietic cells in a growth medium comprising a human flt-3 receptor agonist polypeptide comprising a modified flt-3 ligand amino acid sequence selected from the group consisting of:    (i) the sequence of SEQ ID NO: 144; and    (ii) a polypeptide comprising residues 1-132 of SEQ ID NO:144;    wherein the modification comprises the linear rearrangement of the sequences of (i) or (ii); 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, 87-88, 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 the flt-3 receptor agonist polypeptide is immediately preceded by (methionine −1 ), (alanine −1 ) or (methionine −2 , alanine −1 );    (c) harvesting the cultured cells; and    (d) transplanting the cultured cells into the patient.    
     
     
         9 . A method for treatment of a patient having a hematopoietic disorder, comprising the steps of: 
 (a) removing hematopoietic cells from the patient;    (b) separating hematopoietic cells from other cells;    (c) culturing the separated hematopoietic cells in a growth medium comprising a composition including a pharmaceutically acceptable carrier and a human flt-3 receptor agonist polypeptide comprising a modified flt-3 ligand amino acid sequence selected from the group consisting of:    (i) the sequence of SEQ ID NO: 144; and    (ii) a polypeptide comprising residues 1-132 of SEQ ID NO:144;    wherein the modification comprises the linear rearrangement of the sequences of (i) or (ii); 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, 87-88, 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 the flt-3 receptor agonist polypeptide is immediately preceded by (methionine −1 ), (alanine −1 ) or (methionine −2 , alanine −1 );    (d) harvesting the cultured cells; and    (e) transplanting the cultured cells into the patient.    
     
     
         10 . A method of human gene therapy comprising the steps of: 
 (a) removing hematopoietic cells from a patient;    (b) culturing the hematopoietic cells in a growth medium comprising a human flt-3 receptor agonist polypeptide comprising a modified flt-3 ligand amino acid sequence selected from the group consisting of:    (i) the sequence of SEQ ID NO: 144; and    (ii) a polypeptide comprising residues 1-132 of SEQ ID NO:144;    wherein the modification comprises the linear rearrangement of the sequences of (i) or (ii); 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, 87-88, 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 the flt-3 receptor agonist polypeptide is immediately preceded by (methionine −1 ), (alanine −1 ) or (methionine −2 , alanine −1 );    (c) transducing the cultured cells with DNA;    (d) harvesting the transduced cells; and    (e) transplanting the transduced cells into the patient.    
     
     
         11 . A method of human gene therapy comprising the steps of: 
 (a) removing hematopoietic cells from a patient;    (b) separating the hematopoietic cells from other cells;    (c) culturing the separated hematopoietic cells in a growth medium comprising a human flt-3 receptor agonist polypeptide comprising a modified flt-3 ligand amino acid sequence selected from the group consisting of:    (i) the sequence of SEQ ID NO: 144; and    (ii) a polypeptide comprising residues 1-132 of SEQ ID NO:144;    wherein the modification comprises the linear rearrangement of the sequences of (i) or (ii); 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, 87-88, 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 the flt-3 receptor agonist polypeptide is immediately preceded by (methionine −1 ), (alanine −1 ) or (methionine −2 , alanine −1 ) ;    (d) transducing the cultured cells with DNA;    (e) harvesting the transduced cells; and    (f) transplanting the transduced cells into the patient.    
     
     
         12 . A method of human gene therapy comprising the steps of: 
 (a) removing hematopoietic cells from a patient;    (b) separating the hematopoietic cells from other cells;    (c) culturing the separated hematopoietic cells in a growth medium comprising a composition including a pharmaceutically acceptable carrier and a human flt-3 receptor agonist polypeptide comprising a modified flt-3 ligand amino acid sequence selected from the group consisting of:    (i) the sequence of SEQ ID NO: 144; and    (ii) a polypeptide comprising residues 1-132 of SEQ ID NO:144;    wherein the modification comprises the linear rearrangement of the sequences of (i) or (ii); 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, 87-88, 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 the flt-3 receptor agonist polypeptide is immediately preceded by (methionine −1 ), (alanine −1 ) or (methionine −2 , alanine −1 );    (d) transducing the cultured cells with DNA;    (e) harvesting the transduced cells; and    (f) transplanting the transduced cells into the patient.    
     
     
         13 . A method of human gene therapy comprising the steps of: 
 (a) removing hematopoietic cells from a patient;    (b) separating the hematopoietic cells from other cells;    (c) culturing the separated hematopoietic cells in a growth medium comprising a composition including a pharmaceutically acceptable carrier and a human flt-3 receptor agonist polypeptide comprising a modified flt-3 ligand amino acid sequence selected from the group consisting of:    (i) the sequence of SEQ ID NO: 144; and    (ii) a polypeptide comprising residues 1-132 of SEQ ID NO:144;    wherein the modification comprises the linear rearrangement of the sequences of (i) or (ii); 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, 87-88, 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 the flt-3 receptor agonist polypeptide is immediately preceded by (methionine −1 ), (alanine −1 ) or (methionine −2 , alanine −1 )    (d) transducing the cultured cells with DNA;    (e) harvesting the transduced cells; and    (f) transplanting the transduced cells into the patient.    
     
     
         14 . 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 the hematopoietic progenitor cells or CD34+ cells in a growth medium comprising a human flt-3 receptor agonist polypeptide comprising a modified flt-3 ligand amino acid sequence selected from the group consisting of:    (i) the sequence of SEQ ID NO: 144; and    (ii) a polypeptide comprising residues 1-132 of SEQ ID NO:144;    wherein the modification comprises the linear rearrangement of the sequences of (i) or (ii); 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, 87-88, 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 the flt-3 receptor agonist polypeptide is immediately preceded by (methionine −1 ), (alanine −1 ) or (methionine −2 , alanine −1 ).    
     
     
         15 . The method of  claim 14  further comprising the step of pulsing the culturing hematopoietic progenitor cells or CD34+cells with an antigen.  
     
     
         16 . The method of  claim 14  wherein the growth medium further comprises one or more factors 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.  
     
     
         17 . The method of  claim 15  wherein the growth medium further comprises one or more factors 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.  
     
     
         18 . A method for treating a human having a tumor, infection or auto-immune disease comprising the step of administering a human flt-3 receptor agonist polypeptide comprising a modified flt-3 ligand amino acid sequence selected from the group consisting of: 
 (i) the sequence of SEQ ID NO: 144; and    (ii) a polypeptide comprising residues 1-132 of SEQ ID NO:144;    wherein the modification comprises the linear rearrangement of the sequences of (i) or (ii); 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, 87-88, 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 the flt-3 receptor agonist polypeptide is immediately preceded by (methionine −1 ), (alanine −1 ) or (methionine −2 , alanine −1 ) to the human.    
     
     
         19 . The method of  claim 18  further comprising administrating one or more factors 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.  
     
     
         20 . The method of  claim 18  further comprising the step of administering an antigen to the patient.  
     
     
         21 . The method of  claim 19  further comprising the step of administering an antigen to the patient.  
     
     
         22 . A method for treating a human having a tumor, infection or auto-immune disease, comprising the steps of: 
 (a) mobilizing dendritic cell progenitors or mature dendritic cells by administering a human flt-3 receptor agonist polypeptide comprising a modified flt-3 ligand amino acid sequence selected from the group consisting of:    (i) the sequence of SEQ ID NO: 144; and    (ii) a polypeptide comprising residues 1-132 of SEQ ID NO:144;    wherein the modification comprises the linear rearrangement of the sequences of (i) or (ii); 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, 87-88, 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 the flt-3 receptor agonist polypeptide is immediately preceded by (methionine −1 ), (alanine −1 ) or (methionine −2 , alanine −1 ) to the human;    (b) removing the dendritic cell precursors or mature dendritic cells by a blood draw or pheresis;    (c) pulsing the dendritic cell precursors or mature dendritic cells with an antigen; and    (d) returning the antigen pulsed dendritic cell precursors or mature dendritic cells to the human.    
     
     
         23 . The method of  claim 22  further comprising administering in step (a) one or more factors 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.  
     
     
         24 . The method of  claim 22  further comprising the step of culturing said dendritic cell precursors or mature dendritic cells from step (b) in a growth medium comprising the human flt-3 receptor agonist polypeptide.  
     
     
         25 . The method of  claim 23  further comprising the step of culturing the dendritic cell precursors or mature dendritic cells from step (b) in a growth medium comprising the human flt-3 receptor agonist polypeptide.  
     
     
         26 . The method of  claim 24  wherein the growth medium further comprises one or more factors 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.  
     
     
         27 . The method of  claim 25  wherein the growth medium further comprises one or more factors 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.  
     
     
         28 . 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 the human by a blood draw or pheresis;    (b) culturing the hematopoietic progenitor cells or CD34+cells in a growth medium comprising a human flt-3 receptor agonist polypeptide comprising a modified flt-3 ligand amino acid sequence selected from the group consisting of:    (i) the sequence of SEQ ID NO: 144; and    (ii) a polypeptide comprising residues 1-132 of SEQ ID NO:144;    wherein the modification comprises the linear rearrangement of the sequences of (i) or (ii); 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, 87-88, 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 the flt-3 receptor agonist polypeptide is immediately preceded by (methionine −1 ), (alanine −1 ) or (methionine −2 , alanine −1 ) to produce dendritic cell precursors or mature dendritic cells; and    (c) returning the dendritic cell precursors or mature dendritic cells to the human.    
     
     
         29 . 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 the patient by a blood draw or pheresis;    (b) culturing the hematopoietic progenitor cells or CD34+ cells in a growth medium comprising a human flt-3 receptor agonist polypeptide comprising a modified flt-3 ligand amino acid sequence selected from the group consisting of:    (i) the sequence of SEQ ID NO: 144; and    (ii) a polypeptide comprising residues 1-132 of SEQ ID NO:144;    wherein the modification comprises the linear rearrangement of the sequences of (i) or (ii); 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, 87-88, 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 the flt-3 receptor agonist polypeptide is immediately preceded by (methionine −1 ), (alanine −1 ) or (methionine −2 , alanine −1 ) to produce dendritic cell precursors or mature dendritic cells;    (c) pulsing the dendritic cell precursors or mature dendritic cells with an antigen; and    (d) returning the antigen pulsed dendritic cell precursors or mature dendritic cells to the human.    
     
     
         30 . The method of  claim 28  further comprising the step of separating the hematopoietic progenitor cells or CD34+ cells from other cells prior to culturing.  
     
     
         31 . The method of  claim 29  further comprising the step of separating the hematopoietic progenitor cells or CD34+ cells from other cells prior to culturing.  
     
     
         32 . The method of  claim 28  wherein the culture medium further comprises one or more factors 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 29  wherein the culture medium further comprises one or more factors 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.  
     
     
         34 . The method of  claim 30  wherein the culture medium further comprises one or more factors 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.  
     
     
         35 . The method of  claim 31  wherein the culture medium further comprises one or more factors 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.