Chemically modified polypeptides

1. A method of treating a patient having reduced granulocytes or thrombocytes, which comprises administering to said patient an effective amount of a chemically modified polypeptide having a granulocyte colony-stimulating factor activity in which the hydroxyl group of at least one serine residue is modified with a polyalkylene glycol derivative, said polypeptide comprising a sequence selected from the group consisting of SEQ ID NOs: 1-13, said method resulting in an increase in the number of granulocytes or thrombocytes in said patient.

2. The method according to claim 1 , wherein the polyalkylene glycol derivative has a molecular weight of 500 to 1,000,000.

3. The method according to claim 1 , wherein the polypeptide is modified with a chemical modifying agent comprising a polyalkylene glycol derivative.

4. The method according to claim 3 , wherein the chemical modifying agent is a polyalkylene glycol derivative represented by the following formula (I):

R 1 -(M) n -X—R 2   (I)

wherein R 1 represents an alkyl group or an alkanoyl group; M represents

—OCH 2 CH 2 —, —OCH 2 CH 2 CH 2 — or

—(OCH 2 CH 2 ) r —(OCH 2 CH 2 CH 2 ) s

wherein r and s are the same or different, and each represents an optionally changeable positive integer; n is an optionally changeable positive integer; X represents a bond, O, NH or S; and R 2 represents

wherein R 3 represents OH, halogen or

—X a -(M a ) na —R 1a

wherein X a , M a , R 1a and na each have the same meanings as the above X, M, R 1 and n, respectively; and Y represents halogen or

-Z-(CH 2 ) p —(O) m W

wherein Z represents O, S or NH; and W represents a carboxyl group or a reactive derivative thereof, or

wherein R 4 represents an alkyl group, and Hal represents halogen; p is an integer of 0 to 6; and m is 0 or 1,

—(CO) m —(CH 2 ) t -W

wherein t is an integer of 0 to 6,

wherein Hal a , pa and R 4a each has the same meanings as the above Hal, p and R 4 , respectively,

wherein R 5 represents a residue in which an amino group and a carboxyl group are removed from an amino acid.

5. The method according to claim 3 , wherein the chemical modifying agent is a polyalkylene glycol derivative represented by the following formula (Ib):

wherein W a represents a carboxyl group or a reactive derivative thereof.

6. The method according to claim 1 , wherein the chemically modified polypeptide having a granulocyte colony-stimulating factor activity in which the hydroxyl group of at least one serine residue is modified with a polyalkylene glycol derivative, said polypeptide comprising a sequence selected from the group consisting of SEQ ID NOs: 1-13, wherein said sequence selected from the group consisting of SEQ ID NOs: 1-13 has been chemically modified at serine position 66 from the N-terminus with a polyalkylene glycol derivative.

7. The method according to claim 6 , wherein the polyalkylene glycol derivative has a molecular weight of 500 to 1,000,000.

8. The method according to claim 6 , wherein the polypeptide is modified with a chemical modifying agent comprising a polyalkylene glycol derivative.

9. The method according to claim 8 , wherein the chemical modifying agent is a polyalkylene glycol derivative represented by the following formula (I):

R 1 —(M) n -X—R 2   (I)

wherein R 1 represents an alkyl group or an alkanoyl group; M represents

—OCH 2 CH 2 —, —OCH 2 CH 2 CH 2 — or

—(OCH 2 CH 2 ) r —(OCH 2 CH 2 CH 2 ) s —

wherein r and s are the same or different, and each represents an optionally changeable positive integer; n is an optionally changeable positive integer; X represents a bond, O, NH or S; and R 2 represents

wherein R 3 represents OH, halogen or

—X a -(M a ) na -R 1a

wherein X a , M a , R 1a and na each have the same meanings as the above X, M, R 1 and n, respectively; and Y represents halogen or

-Z-(CH 2 ) p —(O) m —W

wherein Z represents O, S or NH; and W represents a carboxyl group or a reactive derivative thereof, or

wherein R 4 represents an alkyl group, and Hal represents halogen; p is an integer of 0 to 6; and m is 0 or 1,

—(CO) m —(CH 2 ) t —W

wherein t is an integer of 0 to 6,

wherein Hal a , pa and R 4a each has the same meanings as the above Hal, p and R 4 , respectively,

wherein R 5 represents a residue in which an amino group and a carboxyl group are removed from an amino acid.

10. The method according to claim 8 , wherein the chemical modifying agent is a polyalkylene glycol derivative represented by the following formula (Ib):

wherein W a represents a carboxyl group or a reactive derivative thereof.

11. The method according to any one of claims 1 , 2 - 5 , 6 , and 7 - 10 , wherein the patient having reduced granulocytes or thrombocytes is a patient of granulocytopenia or thrombocytopenia.