Therapeutic agent for patients having human FcgammaRIIIa

• US 20050031613A1
• Filed: 04/09/2003
• Published: 02/10/2005
• Est. Priority Date: 04/09/2002
• Status: Abandoned Application

• Current Assignee: Kyowa Hakko Kirin Company Limited (Kirin Holdings Company Limited)
• Original Assignee: Kyowa Hakko Kirin Company Limited (Kirin Holdings Company Limited)
• Inventors: Okazaki, Akira, Hatanaka, Shigeki, Nakamura, Kazuyasu, Shitara, Kenya, Niwa, Rinpei
• Application Number:
  US10/409,608
• Publication Number:
  US 20050031613A1
• Time in Patent Office: Days
• US Class Current: 424/145.100
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 39/395 Antibodies agglutinins A61K38/36 ; as drug carriers A61K47/50; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07K 16/00 Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies antibodies with enzymatic activity, e.g. abzymes C12N9/0002
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 16/3084 against tumour-associated gangliosides
• CPC Class Codes: C07K 16/44 against material not provided for elsewhere , e.g. haptens, metals, DNA, RNA, amino acids
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/41 Glycosylation, sialylation, or fucosylation
• CPC Class Codes: C07K 2317/52 Constant or Fc region; Isotype
• CPC Class Codes: C07K 2317/732 Antibody-dependent cellular cytotoxicity [ADCC]
• CPC Class Codes: C07K 2319/30 : Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

Abstract

A medicament for treating FcγRIIIa polymorphism patients who cannot be treated by a medicament comprising as an active ingredient an antibody composition produced by a cell unresistant to a lectin which recognizes a sugar chain in which 1-position of fucose is bound to 6-position of N-acetylglucosamine in the reducing end through α-bond in a complex N-glycoside-linked sugar chain, which comprises as an active ingredient an antibody composition produced by a cell resistant to a lectin which recognizes a sugar chain in which 1-position of fucose is bound to 6-position of N-acetylglucosamine in the reducing end through α-bond in a complex N-glycoside-linked sugar chain.

Claims

1. A medicament for treating a patient who exerts such an affinity of a medicament comprising as an active ingredient an antibody composition produced by a cell unresistant to a lectin which recognizes a sugar chain in which 1-position of fucose is bound to 6-position of N-acetylglucosamine in the reducing end through α

-bond in a complex N-glycoside-linked sugar chain with a human Fcγ

receptor IIIa that it is not enough for the antibody composition to exert sufficient therapeutic effect, which comprises as an active ingredient an antibody composition produced by a cell resistant to a lectin which recognizes a sugar chain in which 1-position of fucose is bound to 6-position of N-acetylglucosamine in the reducing end through α

-bond in a complex N-glycoside-linked sugar chain.

2. The medicament according to claim 1, wherein the affinity that it is not enough to exert sufficient therapeutic effect is an affinity that is not enough for the antibody composition to exert a sufficient antibody-dependent cell-mediated cytotoxic activity.

3. The medicament according to claim 1, wherein the affinity that it is not enough to exert sufficient therapeutic effect is lower than at least one affinity selected from the group consisting of (a) and (b):

(a) a binding constant to the human Fcγ

receptor IIIa at 25°

C. being 1×

10⁷ M<sup>−

1</sup> when measured by a biosensor method according to BIAcore;

(b) a binding constant to the human Fcγ

receptor IIIa at 25°

C. being 2×

10⁶ M<sup>−

1</sup> when measured with an isothermal titration-type calorimeter.

4. The medicament according to claim 1, wherein the human Fcγ

receptor IIIa is a human Fcγ

receptor IIIa in which an amino acid residue at position 176 from the N-terminal methionine in the signal sequence is phenylalanine.

5. The medicament according to claim 1 wherein the patient is a patient having a human Fcγ

receptor IIIa in which an amino acid residue at position 176 from the N-terminal methionine in the signal sequence is phenylalanine.

6. The medicament according to claim 1, wherein the patient is a patient having only human Fcγ

receptor IIIa in which an amino acid residue at position 176 from the N-terminal methionine in the signal sequence is phenylalanine.

7. The medicament according to claim 1, wherein the cell resistant to the lectin is a cell, in which the activity of a protein is decreased or deleted, selected from the group consisting of the following (a), (b) and (c):

(a) an enzyme protein relating to synthesis of an intracellular sugar nucleotide, GDP-fucose;

(b) an enzyme protein relating to modification of a sugar chain in which 1-position of fucose is bound to 6-position of N-acetylglucosamine in the reducing end through α

-bond in a complex N-glycoside-linked sugar chain;

(c) a protein relating to transport of an intracellular sugar nucleotide, GDP-fucose to the Golgi body.

8. The medicament according to claim 1, wherein the lection is selected from the group consisting of the following (a) to (d):

(a) a Lens culinaris lectin;

(b) a Pisum sativum lectin;

(c) a Vicia faba lectin;

(d) an Aleuria aurantia lectin.

9. The medicament according to claim 1, wherein the cell is selected from the group consisting of a yeast, an animal cell, an insect cell and a plant cell.

10. The medicament according to claim 1, wherein the cell is selected from the group consisting of the following (a) to (j):

(a) a CHO cell derived from a Chinese hamster ovary tissue;

(b) a rat myeloma cell line YB2/3HL.P2.G11.16Ag.20 line;

(d) a mouse myeloma cell line NS0 cell;

(d) a mouse myeloma cell line SP2/0-Ag14 cell;

(e) a BHK cell derived from a Syrian hamster kidney tissue;

(f) a hybridoma cell;

(g) a human leukemic cell line Namalwa cell;

(h) an embryonic stem cell;

(i) a fertilized egg cell;

(j) a plant cell.

11. The medicament according to claim 1, wherein the antibody composition which comprises as an active ingredient the antibody molecule is selected from the group consisting of the following (a) to (d):

(a) a human antibody;

(b) a humanized antibody;

(c) an antibody fragment comprising the Fc region of (a) or (b);

(d) a fusion protein comprising the Fc region of (a) or (b).

12. The medicament according to claim 11, wherein the antibody molecule belongs to an IgG class.

13. The medicament according to claim 1, wherein the antibody composition produced by a cell resistant to a lectin which recognizes a sugar chain in which 1-position of fucose is bound to 6-position of N-acetylglucosamine in the reducing end through α

-bond in a complex N-glycoside-linked sugar chain is an antibody composition having a higher antibody-dependent cell-mediated cytotoxic activity than the antibody composition produced by a cell unresistant to a lectin which recognizes a sugar chain in which 1-position of fucose is bound to 6-position of N-acetylglucosamine in the reducing end through α

-bond in a complex N-glycoside-linked sugar chain.

14. The medicament according to claim 13, wherein the antibody composition having a higher antibody-dependent cell-mediated cytotoxic activity has a higher ratio of a sugar chain in which fucose is not bound to N-acetylglucosamine in the reducing end in the sugar chain among total complex N-glycoside-linked sugar chains bound to the Fc region in the antibody composition than the antibody composition produced by a cell unresistant to a lectin which recognizes a sugar chain in which 1-position of fucose is bound to 6-position of N-acetylglucosamine in the reducing end through α

-bond in a complex N-glycoside-linked sugar chain.

15. The medicament according to claim 14, wherein the sugar chain in which fucose is not bound is a sugar chain in which 1-position of the fucose is not bound to 6-position of N-acetylglucosamine in the reducing end through α

-bond in a complex N-glycoside-linked sugar chain.

16. The medicament according to claim 13, wherein the antibody composition having a higher antibody-dependent cell-mediated cytotoxic activity is an antibody composition having a ratio of a sugar chain in which fucose is not bound to N-acetylglucosamine in the reducing end in the sugar chain of 20% or more of total complex N-glycoside-linked sugar chains bound to the Fc region in the antibody composition.

17. The medicament according to claim 16, wherein the antibody composition is an antibody composition produced by a CHO cell.

18. The medicament according to claim 1, which is a diagnostic agent, an preventing agent or a therapeutic agent for tumor-accompanied diseases, allergy-accompanied diseases, inflammatory-accompanied diseases, autoimmune diseases, cardiovascular diseases, viral infection-accompanied diseases or bacterial infection-accompanied diseases.

20. A method for screening a patient to which the medicament according to claim 1 is effective, which comprises:

(i) contacting a medicament comprising as an active ingredient an antibody composition produced by a cell unresistant to a lectin which recognizes a sugar chain in which 1-position of fucose is bound to 6-position of N-acetylglucosamine in the reducing end through α

-bond in a complex N-glycoside-linked sugar chain or the medicament according to with claim 1, with an effector cell obtained from a patient;

(ii) measuring the amount of each of the medicaments bound to the effector cell;

(iii) comparing the measured amounts;

(iv) selecting a patient in which the amount of the medicament comprising as an active ingredient an antibody composition produced by a cell unresistant to a lectin which recognizes a sugar chain in which 1-position of fucose is bound to 6-position of N-acetylglucosamine in the reducing end through α

-bond in a complex N-glycoside-linked sugar chain which has been added to the effector cell is lower.

21. The method according to claim 20, wherein the method for measuring the amount the medicament bound to the target cell is an immunological measuring method.

22. A method for screening a patient to which the medicament according to claim 1 is effective, which comprises

(i) contacting a medicament comprising as an active ingredient an antibody composition produced by a cell unresistant to a lectin which recognizes a sugar chain in which 1-position of fucose is bound to 6-position of N-acetylglucosamine in the reducing end through α

-bond in a complex N-glycoside-linked sugar chain or the medicament according to claim 1, with an effector cell obtained from a patient;

(ii) measuring the activity caused by the contact of each of the medicaments with the effector cell;

(iii) comparing the measured activities;

(iv) selecting a patient in which the activity of the medicament comprising as an active ingredient an antibody composition produced by a cell unresistant to a lectin which recognizes a sugar chain in which 1-position of fucose is bound to 6-position of N-acetylglucosamine in the reducing end through α

-bond in a complex N-glycoside-linked sugar chain is lower.

23. The method according to claim 22, wherein the method for measuring the activity caused by the contact of the medicament reacted with the target cell is a method selected from the group consisting of (a) to (e):

(a) a method for measuring an antibody-dependent cell-mediated cytotoxic activity;

(b) a method for measuring a complement-dependent cytotoxic activity;

(c) a method for measuring expression of a cytotoxic molecule;

(d) a method for measuring an intracellular signal transduction of a human Fcγ

receptor IIIa;

(e) a method for measuring a molecule of which expression is varied by stimulating a human Fcγ

receptor IIIa.

24. The method according to claim 20, wherein the effector cell is a cell which expresses a human Fcγ

receptor IIIa.

25. The method according to claim 20, wherein the screening method is a method for screening a patient having a human Fcγ

receptor IIIa in which an amino acid residue at position 176 from the N-terminal methionine in the signal sequence is phenylalanine.

26. A medicament which comprises as an active ingredient an antibody composition produced by a cell resistant to a lectin which recognizes a sugar chain in which 1-position of fucose is bound to 6-position of N-acetylglucosamine in the reducing end through α

-bond in a complex N-glycoside-linked sugar chain and is administered to a patient having a human Fcγ

receptor IIIa in which an amino acid residue at position 176 from the N-terminal methionine in the signal sequence is phenylalanine who is screened by the method according to claim 20.

27. The medicament according to claim 1, which is administered to a patient having a human Fcγ

receptor IIIa in which an amino acid residue at position 176 from the N-terminal methionine in the signal sequence is phenylalanine who is screened by the method according to claim 20.

29. The method according to claim 22, wherein the effector cell is a cell which expresses a human Fcγ

receptor IIIa.

30. The method according to claim 22, wherein the screening method is a method for screening a patient having a human Fcγ

receptor IIIa in which an amino acid residue at position 176 from the N-terminal methionine in the signal sequence is phenylalanine.

31. A medicament which comprises as an active ingredient an antibody composition produced by a cell resistant to a lectin which recognizes a sugar chain in which 1-position of fucose is bound to 6-position of N-acetylglucosamine in the reducing end through α

-bond in a complex N-glycoside-linked sugar chain and is administered to a patient having a human Fcγ

receptor IIIa in which an amino acid residue at position 176 from the N-terminal methionine in the signal sequence is phenylalanine who is screened by the method according to claim 22.

32. The medicament according to claim 1, which is administered to a patient having a human Fcγ

receptor IIIa in which an amino acid residue at position 176 from the N-terminal methionine in the signal sequence is phenylalanine who is screened by the method according to claim 22.

19. (Cancelled)

28. (Cancelled)