Modified Fc molecules

• US 7,750,127 B2
• Filed: 08/01/2008
• Issued: 07/06/2010
• Est. Priority Date: 09/24/2004
• Status: Active Grant

• Current Assignee: Amgen Inc.
• Original Assignee: Amgen Inc.
• Inventors: Xiong, Fei, Sitney, Karen C., Gegg, Colin
• Primary Examiner(s): HUFF, SHEELA JITENDRA
• Application Number:
  US12/221,413
• Publication Number:
  US 20090281286A1
• Time in Patent Office: 704 Days
• Field of Search: None
• US Class Current: 530/391.7
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/06 Anabolic agents androgens A61P5/26
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 7/06 Antianaemics
• 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 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/52 Constant or Fc region; Isotype
• CPC Class Codes: C07K 2318/10 Immunoglobulin or domain(s) thereof as scaffolds for inserted non-Ig peptide sequences, e.g. for vaccination purposes
• 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

The present invention concerns compositions of matter, for example, but not limited to, modified antibodies, in which one or more biologically active peptides are incorporated into a loop region of a non-terminal domain of an immunoglobulin Fc domain.

Claims

1. A composition of matter of the formula

(X¹)_a—

F¹—

(X²)_b

and multimers thereof, wherein;

F¹ is an IgG3 Fc domain comprising SEQ ID NO;

605 modified so that it comprises at least one X³ inserted into or replacing all or part of a sequence selected from SEQ ID NOS;

614, 621, 622, 624, 627, 639, 641, 644, 645 and 646 within a loop region of the IgG3 Fc domain, said loop region being in a non-terminal domain of the Fc domain;

X¹ and X² are each independently selected from -(L¹)_c-P¹, -(L¹)_c-P¹-(L²)_d-P², -(L¹)_c-P¹-(L²)_d-P²-(L³)_e-P³, and -(L¹ )_c-P¹-(L²)_d-P²-(L³)_e-P³-(L⁴)_f-P⁴;

X³ is independently selected from -(L⁵)_c-P⁵, -(L⁵)_c-P⁵-(L⁶)_d-P⁶, -(L⁵)_c-P⁵-(L⁶)_d-P⁶-(L⁷)_e-P⁷, and -(L⁵)_c-P⁵-(L⁶)_d-P⁶-(L⁷)_e-P⁷-(L⁸)_f-P⁸;

P¹, P², P³, and P⁴ are each independently sequences of pharmacologically active polypeptides or pharmacologically active peptides;

P⁵, P⁶, P⁷, and P⁸ are each independently sequences of pharmacologically active peptides;

L¹, L², L³, L⁴, L⁵, L⁶, L⁷, and L⁸ are each independently linkers; and

a, b, c, d, e, and f are each independently 0 or 1.

2. The composition of matter of claim 1, wherein X³ is inserted at H₁₀₀/E₁₀₁, F₁₂₈/N₁₂₉, N₁₅₇/K₁₅₈, M₁₉₀/T₁₉₁, Q₂₁₈/P₂₁₉, E₂₂₀/N₂₂₁, S₂₃₂/D₂₃₃, G₂₃₄/S₂₃₅, or G₂₅₂/N₂₅₃.

3. The composition of matter of claim 1, wherein X³ comprises a myostatin binding peptide sequence, an erythropoietin-mimetic (EPO-mimetic) peptide sequence, an angiotensin-2 (ang-2) binding peptide sequence, a thrombopoietin-mimetic (TPO-mimetic) peptide sequence, an angiotensin-2 (ang-2) binding peptide sequence, a nerve growth factor (NGF) binding peptide sequence, or a B cell activating factor (BAFF) binding peptide sequence.

4. The composition of matter of claim 3, wherein the myostatin binding peptide sequence is selected from SEQ ID NOS:

218 to 509.

5. The composition of matter of claim 3, wherein the EPO-mimetic peptide sequence is selected from SEQ ID NOS:

1 to 27.

6. The composition of matter of claim 3, wherein the TPO-mimetic peptide sequence is selected from SEQ ID NOS:

28 to 99.

7. The composition of matter of claim 3, wherein the ang-2 binding peptide sequence is selected from SEQ ID NOS:

100 to 189.

8. The composition of matter of claim 3, wherein the NGF binding peptide sequence is selected from SEQ ID NOS:

190 to 218.

9. The composition of matter of claim 3, wherein the BAFF binding peptide sequence is selected from SEQ ID NOS:

510 to 594.

10. A modified antibody, comprising an Fc domain, F¹, wherein:

F¹ is an IgG3 Fc domain comprising SEQ ID NO;

605 modified so that it comprises at least one X³ inserted into or replacing all or part of a sequence selected from SEQ ID NOS;

614, 621, 622, 624, 627, 639, 641, 644, 645 and 646 within a loop region of the lgG3 Fc domain, said loop region being in a non-terminal domain of the Fc domain, wherein;

X³ is independently selected from -(L⁵)_c-P⁵, -(L⁵)_c-P⁵-(L⁶)_d-P⁶, -(L⁵)_c-P⁵-(L⁶)_d-P⁶-(L⁷)_e-P⁷, and -(L⁵)_c-P⁵-(L⁶)_d-P⁶-(L⁷)_e-P⁷-(L⁸)_f-P⁸;

P⁵, P⁶, P⁷, and P⁸ are each independently sequences of pharmacologically active peptides;

L⁵, L⁶, L⁷, and L⁸ are each independently linkers; and

c, d, e, and f are each independently 0 or 1.

11. The modified antibody of claim 10, wherein X³ is inserted at H₁₀₀/E₁₀₁, F₁₂₈/N₁₂₉, N₁₅₇/K₁₅₈, M₁₉₀/T₁₉₁, Q₂₁₈/P₂₁₉, E₂₂₀/N₂₂₁, S₂₃₂/D₂₃₃, G₂₃₄/S₂₃₅, or G₂₅₂/N₂₅₃.

12. The modified antibody of claim 10, wherein X³ comprises a myostatin binding peptide sequence, an erythropoietin-mimetic (EPO-mimetic) peptide sequence, a thrombopoietin-mimetic (TPO-mimetic) peptide sequence, an angiotensin-2 (ang-2) binding peptide sequence, a nerve growth factor (NGF) binding peptide sequence, or a B cell activating factor (BAFF) binding peptide sequence.

13. The modified antibody of claim 12, wherein the myostatin binding peptide sequence is selected from SEQ ID NOS:

218 to 509.

14. The modified antibody of claim 12, wherein the EPO-mimetic peptide sequence is selected from SEQ ID NOS:

1 to 27.

15. The modified antibody of claim 12, wherein the TPO-mimetic peptide sequence is selected from SEQ ID NOS:

28 to 99.

16. The modified antibody of claim 12, wherein the ang-2 binding peptide sequence is selected from SEQ ID NOS:

100 to 189.

17. The modified antibody of claim 12, wherein the NGF binding peptide sequence is selected from SEQ ID NOS:

190 to 218.

18. The modified antibody of claim 12, wherein the BAFF binding peptide sequence is selected from SEQ ID NOS:

510 to 594.