Alteration of FcRn binding affinities or serum half-lives of antibodies by mutagenesis

• US 20050014934A1
• Filed: 04/09/2004
• Published: 01/20/2005
• Est. Priority Date: 10/15/2002
• Status: Active Grant

• Current Assignee: Abbott Biotherapeutics Corp. (Abbott Laboratories Incorporated)
• Original Assignee: PDL BioPharma, Inc.
• Inventors: Vasquez, Maximiliano, Hinton, Paul R., Tsurushita, Naoya, Tso, J. Yun
• Granted Patent: US 7,361,740 B2
• Time in Patent Office: Days
• US Class Current: 530/387.300
• 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 16/082 Hepadnaviridae, e.g. hepatitis B virus
• CPC Class Codes: C07K 16/249 Interferons
• CPC Class Codes: C07K 16/2809 against the T-cell receptor (TcR)-CD3 complex
• CPC Class Codes: C07K 16/2833 against MHC-molecules, e.g. HLA-molecules
• CPC Class Codes: C07K 16/2866 against receptors for cytokines, lymphokines, interferons
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/52 Constant or Fc region; Isotype
• CPC Class Codes: C07K 2317/732 Antibody-dependent cellular cytotoxicity [ADCC]

Abstract

The present invention provides for a modified antibody of class IgG, in which at least one amino acid from the heavy chain constant region selected from the group consisting of amino acid residues 250, 314, and 428 is substituted with another amino acid which is different from that present in the unmodified antibody, thereby altering the binding affinity for FcRn and/or the serum half-life in comparison to the unmodified antibody.

Claims

1. A modified antibody of class IgG wherein at least one amino acid residue from the heavy chain constant region selected from the group consisting of amino acid residues 250, 314, and 428 is different from that present in an unmodified class IgG antibody, wherein the FcRn binding affinity and/or serum half-life of said modified antibody is altered relative to that of the unmodified antibody.

2. The modified antibody according to claim 1, wherein said unmodified class IgG antibody is selected from the group consisting of daclizumab, fontolizumab, visilizumab and M200.

3. An antibody having a constant region substantially identical to that of a naturally occurring class IgG antibody wherein at least one amino acid residue from the heavy chain constant region selected from the group consisting of residues 250, 314, and 428 is different from that present in the naturally occurring class IgG antibody, wherein the FcRn binding affinity and/or serum half-life of said antibody is altered relative to the naturally occurring antibody.

4. The antibody according to claim 3 wherein said naturally occurring class IgG antibody is selected from the group consisting of daclizumab, fontolizumab, visilizumab and M200.

5. The antibody according to claim 3, wherein:

(a) said amino acid residue 250 from the heavy chain constant region is glutamic acid or glutamine;

or

(b) said amino acid residue 428 from the heavy chain constant region is phenylalanine or leucine.

6. The antibody according to claim 3, wherein said amino acid residue 250 from the heavy chain constant region is glutamine.

7. The antibody according to claim 3, wherein said amino acid residue 428 from the heavy chain constant region is leucine.

8. The antibody according to claim 3, wherein:

(a) said amino acid residue 250 from the heavy chain constant region is glutamic acid and said amino acid residue 428 from the heavy chain constant region is phenylalanine;

(b) said amino acid residue 250 from the heavy chain constant region is glutamine and said amino acid residue 428 from the heavy chain constant region is phenylalanine;

or

(c) said amino acid residue 250 from the heavy chain constant region is glutamine and said amino acid residue 428 from the heavy chain constant region is leucine.

9. A modified therapeutic antibody of class IgG with an in vivo elimination half-life at least about 1.3-fold longer than that of the corresponding unmodified class IgG antibody.

10. The modified therapeutic antibody of class IgG of claim 9, wherein at least one amino acid residue from the heavy chain constant region selected from the group consisting of residues 250, 314, and 428 is different from that present in the unmodified antibody.

11. The modified therapeutic antibody of class IgG of claim 9, wherein the antibody is selected from the group consisting of daclizumab, fontolizumab, visilizumab and M200.

12. The modified therapeutic antibody of class IgG of claim 9, wherein:

(a) said amino acid residue 250 from the heavy chain constant region is glutamic acid and amino acid residue 428 from the heavy chain constant region is phenylalanine;

(b) said amino acid residue 250 from the heavy chain constant region is glutamine and amino acid residue 428 from the heavy chain constant region is phenylalanine;

or (c) said amino acid residue 250 from the heavy chain constant region is glutamine and amino acid residue 428 from the heavy chain constant region is leucine.

13. A modified therapeutic antibody of class IgG with an in vivo clearance at least about 1.3-fold lower than that of the corresponding unmodified class IgG antibody.

14. The modified therapeutic antibody of class IgG of claim 13, wherein at least one of amino acid residue from the heavy chain constant region selected from the group consisting of residues 250, 314, and 428 is different from that present in the unmodified class IgG antibody.

15. The modified therapeutic antibody of class IgG of claim 13, wherein the antibody is selected from the group consisting of daclizumab, fontolizumab, visilizumab and M200.

16. A modified therapeutic antibody comprising a light chain amino acid sequence of SEQ ID NO:

118 and a heavy chain amino acid sequence selected from SEQ ID NOs;

119-128.

17. A vector comprising a polynucleotide encoding the light or heavy chain amino acid sequence of claim 16.

18. A host cell comprising the vector according to claim 16.

19. A modified therapeutic antibody comprising a light chain amino acid sequence of SEQ ID NO:

129 and a heavy chain amino acid sequence selected from SEQ ID NOs;

130-134.

20. A vector comprising a polynucleotide encoding the light or heavy chain amino acid sequence of claim 19.

21. A host cell comprising the vector according to claim 19.

22. A modified therapeutic antibody comprising a light chain amino acid sequence of SEQ ID NO:

135 and a heavy chain amino acid sequence selected from SEQ ID NOs;

136-140.

23. A vector comprising a polynucleotide encoding the light or heavy chain amino acid sequence of claim 22.

24. A host cell comprising the vector according to claim 22.

25. A modified therapeutic antibody comprising a light chain amino acid sequence of SEQ ID NO:

141 and a heavy chain amino acid sequence selected from SEQ ID NOs;

142-146.

26. A vector comprising a polynucleotide encoding the light or heavy chain amino acid sequence of claim 25.

27. A host cell comprising the vector according to claim 25.