CA2580796A1 - Modified fc molecules having peptides inserted in internal loop regions - Google Patents

Modified fc molecules having peptides inserted in internal loop regions Download PDF

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Publication number
CA2580796A1
CA2580796A1 CA002580796A CA2580796A CA2580796A1 CA 2580796 A1 CA2580796 A1 CA 2580796A1 CA 002580796 A CA002580796 A CA 002580796A CA 2580796 A CA2580796 A CA 2580796A CA 2580796 A1 CA2580796 A1 CA 2580796A1
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matter
composition
domain
seq
sequence
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CA002580796A
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French (fr)
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CA2580796C (en
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Colin V. Gegg
Fei Xiong
Karen C. Sitney
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Amgen Inc
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Amgen Inc.
Colin V. Gegg
Fei Xiong
Karen C. Sitney
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/06—Anabolic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/475—Growth factors; Growth regulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2318/00—Antibody mimetics or scaffolds
    • C07K2318/10—Immunoglobulin or domain(s) thereof as scaffolds for inserted non-Ig peptide sequences, e.g. for vaccination purposes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

Abstract

The present invention concerns molecules and a process in which one or more biologically active peptides are incorporated into an Fc domain. In this invention, pharmacologically active compounds may be prepared by a process comprising (a) selecting at least one peptide that modulates the activity of a protein of interest; and (b) preparing a pharmacologic agent comprising an amino acid sequence of the selected peptide in a loop region of an Fc domain.
This process may be employed to modify an Fc domain that is already linked through an N- or C-terminus or sidechain to a peptide or to a polypeptide (e.g., etanercept). This process may also be employed to modify an Fc domain that is part of an antibody (e.g., adalimumab, epratuzumab, infliximab, Herceptin~, and the like). In this way, different molecules can be produced that have additional functionalities, such as a binding domain to a different epitope or an additional binding domain to the precursor molecule's existing epitope. The peptide can be selected, for example, by phage display, E. coli display, ribosome display, RNA-peptide screening, yeast-based screening, chemical-peptide screening, rational design, or protein structural analysis.

Claims (62)

1. A composition of matter of the formula (X1)a-F1-(X2)b and multimers thereof, wherein:
F1 is an Fc domain modified so that it comprises at least one X3 in a loop region, 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)c-P3, and -(L1)c-P1-(L2)d-P2-(L3)C-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)c-P7, and -(L5)c-P-(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 a and b are each 0.
3. The composition of matter of Claim 1 wherein the Fc domain comprises art IgG Fc domain.
4. The composition of matter of Claim 3 wherein the Fc domain comprises a sequence selected from SEQ ID NOS: 599 and 603 to 607.
5. The composition of matter of Claim 1 wherein the Fc domain comprises an IgG1 Fc domain.
6. The composition of matter of Claim 5 wherein the IgG1 Fc domain comprises SEQ ID NO: 599 and X3 is inserted into or replaces all or part of a sequence selected from SEQ ID NOS: 621, 622, 624, 625, 627, 628, 630, 632, 634, and 636.
7. The composition of matter of Claim 6 wherein X3 is inserted into or replaces all or part of a sequence selected from SEQ ID NOS: 623, 626, 629, 631, 633, 635, and 637.
8. The composition of matter of Claim 7 wherein X3 is inserted at Leu139/Thr140.
9. The composition of matter of Claim 5 wherein the IgG1 Fc domain comprises SEQ ID NO: 603 and X3 is inserted into or replaces all or part of a sequence selected from SEQ ID NOS: 621, 622, 624, 625, 627, 628, 630, 632, 634, and 636.
10. The composition of matter of Claim 9 wherein X3 is inserted at H53/E54, Y81/N82, N110/K111, L143/T144, Q171/P172, E173/N174, S186/D187, G188/S189, or G205/N206.
11. The composition of matter of Claim 5 wherein the IgG1 Fc domain comprises SEQ ID NO: 604 and X3 is inserted into or replaces all or part of a sequence selected from SEQ ID NOS: 621, 622, 624, 625, 627, 628, 632, 634, 636, and 644.
12. The composition of matter of Claim 11 wherein X3 is inserted at H53/E54, Y81/N82/ N110/K111, L143/T144, Q171/P172, E173/N174, S186/D187, G188/S189, or G05 /N206.
13. The composition of matter of Claim 1 wherein the Fc domain comprises an IgG3 Fc domain.
14. The composition of matter of Claim 13 wherein the IgG3 Fc domain comprises SEQ ID NO: 605 and X3 is inserted into or replaces all or part of a sequence selected from SEQ ID NOS: 614, 621, 622, 624, 627, 639, 641, 644, 645, and 646.
15. The composition of matter of Claim 14 wherein X3 is inserted at H100/E101, F128/N129, N157/K158, M190/T191, Q218/P219, E220/N221, S232/D233, G234/S235, or G252/N253.
16. The composition of matter of Claim 1 wherein the Fc domain comprises an IgG2 Fc domain.
17. The composition of matter of Claim 16 wherein the Fc domain comprises SEQ ID NO: 606 and X3 is inserted into or replaces all or part of a sequence selected from SEQ ID NOS: 621, 622, 624, 632, 636, 639, 640, 642, 644, and 646.
18. The composition of matter of Claim 17 wherein X3 is inserted at H49/E50, F77/N78, N106/K107, M139/T140, Q167/P168, E169/N170, S181/D182, G183/S184, or G201/N202.
19. The composition of matter of Claim 1 wherein the Fc domain comprises an IgG4 Fc domain.
20. The composition of matter of Claim 19 wherein the Fc domain comprises SEQ ID NO: 607 and X3 is inserted into or replaces all or part of a sequence selected from SEQ ID NOS: 620, 621, 624, 627, 632, 634, 638, 639, 643, and 644.
21. The composition of matter of Claim 20 wherein X3 is inserted at Q50/E51, F78/N79, N107/K108, M140/T141, Q168/P169, E170/N171, S182/D183, G184/S185, or G202/N203.
22. The composition of matter of Claim 1 wherein the Fc domain comprises SEQ ID NO: 608 and X3 is inserted into or replaces all or part of a sequence selected from SEQ ID NOS: 621, 622, 628, 624, 627, 632, 636, 639, 644, and 646.
23. The composition of matter of Claim 22 wherein X3 is inserted at H112/E113, F140/N141, N169/K170, M204/T205, Q232/P233, E234/N235, S246/D247 G248/S249, or G268/N269.
24. The composition of matter of Claim 1 wherein X3 comprises an angiotensin-2 (ang-2) binding peptide sequence.
25. The composition of matter of Claim 24 wherein the ang-2 binding peptide sequence is selected from SEQ ID NOS: 100 to 189.
26. The composition of matter of Claim 25 wherein the ang-2 binding peptide sequence is SEQ ID NO: 147.
27. The composition of matter of Claim 26 wherein F1 comprises an IgG1 Fc domain.
28. The composition of matter of Claim 27 having the sequence of SEQ ID
NO: 618.
29. The composition of matter of Claim 1 wherein X3 comprises a myostatin binding peptide sequence.
30. The composition of matter of Claim 29 wherein the myostatin binding peptide sequence is selected from SEQ ID NOS: 218 to 509.
31. The composition of matter of Claim 30 wherein the myostatin binding peptide sequence is SEQ ID NO: 365.
32. The composition of matter of Claim 31 wherein F1 comprises an IgG1 Fc domain.
33. The composition of matter of Claim 32 having the sequence SEQ ID
NO: 612.
34. The composition of matter of Claim 1 wherein X3 comprises an erythropoietin-mimetic (EPO-mimetic) peptide sequence.
35. The composition of matter of Claim 34 wherein the EPO-mimetic peptide sequence is selected from SEQ ID NOS: 1 to 27.
36. The composition of matter of Claim 35 wherein the EPO-mimetic peptide sequence is SEQ ID NO: 2.
37. The composition of matter of Claim 36 wherein F1 comprises an IgG1 Fc domain.
38. The composition of matter of Claim 37 having the sequence of SEQ ID
NO: 615.
39. The composition of matter of Claim 1 wherein X3 comprises a thrombopoietin-mimetic (TPO-mimetic) peptide sequence.
40. The composition of matter of Claim 39 wherein the TPO-mimetic peptide sequence is selected from SEQ ID NOS: 28 to 99.
41. The composition of matter of Claim 40 wherein the TPO-mimetic peptide sequence is SEQ ID NO: 28.
42. The composition of matter of Claim 41 wherein F1 comprises an IgG1 Fc domain.
43. The composition of matter of Claim 42 having the sequence SEQ ID
NO: 616.
44. The composition of matter of Claim 1 wherein X3 comprises a nerve growth factor (NGF) binding peptide sequence.
45. The composition of matter of Claim 44 wherein the NGF binding peptide sequence is selected from SEQ ID NOS: 190 to 218.
46. The composition of matter of Claim 1 wherein X3 comprises a B cell activating factor (BAFF) binding peptide sequence.
47. The composition of matter of Claim 46 wherein the BAFF binding peptide sequence is selected from SEQ ID NOS: 510 to 594.
48. A DNA encoding a composition of matter of Claim 1.
49. An expression vector comprising the DNA of Claim 48.
50. A host cell comprising the expression vector of Claim 49.
51. The cell of Claim 50, wherein the cell is an E. coli cell.
52. A process for preparing a pharmacologically active compound, which comprises:
a. selecting at least one randomized peptide that modulates the activity of a protein of interest; and b. preparing a pharmacologic agent comprising an amino acid sequence of the selected peptide as an internal, non-terminal, sequence of an Fc domain.
53. The process of Claim 52, wherein the internal region of the Fc domain is a loop region.
54. The process of Claim 52, wherein the peptide is selected in a process comprising one or more techniques selected from yeast-based screening, rational design, protein structural analysis, or screening of a phage display library, an E. coli display library, a ribosomal library, or a chemical peptide library.
55. The process of Claim 52, wherein the preparation of the pharmacologic agent is carried out by:
a. preparing a gene construct comprising a nucleic acid sequence encoding an Fc domain wherein the amino acid sequence of the selected peptide is inserted into or replaces one or more amino acids within the Fc domain; and b. expressing the gene construct.
56. The process of Claim 55, wherein the gene construct is expressed in an E. coli cell.
57. The process of Claim 52, wherein the protein of interest is a cell surface receptor.
58. The process of Claim 52, wherein the protein of interest has a linear epitope.
59. The process of Claim 52, wherein the protein of interest is a cytokine receptor.
60. The process of Claim 52 wherein the Fc domain is an IgG Fc domain.
61. A modified antibody, comprising an Fc domain modified so that it comprises at least one X3 in a loop region, 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)c-P7, and -(L5)c-P5-(L6)d-P6-(L7)e-P7-(L6)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.
62. A process for preparing a modified antibody, which comprises:
a) selecting at least one peptide that modulates the activity of a protein of interest; and b) preparing an antibody comprising an amino acid sequence of the selected peptide in a loop region of an Fc domain of the antibody, said loop region being in a non-terminal domain of the Fc domain.
CA2580796A 2004-09-24 2005-09-23 Modified fc molecules having peptides inserted in internal loop regions Expired - Fee Related CA2580796C (en)

Applications Claiming Priority (3)

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US61268004P 2004-09-24 2004-09-24
US60/612,680 2004-09-24
PCT/US2005/034273 WO2006036834A2 (en) 2004-09-24 2005-09-23 MODIFIED Fc MOLECULES

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CA2580796A1 true CA2580796A1 (en) 2006-04-06
CA2580796C CA2580796C (en) 2013-03-26

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US (7) US7442778B2 (en)
EP (1) EP1797127B1 (en)
JP (1) JP5017116B2 (en)
KR (1) KR100920282B1 (en)
CN (1) CN101103045B (en)
AU (1) AU2005289685B2 (en)
BR (1) BRPI0516011A (en)
CA (1) CA2580796C (en)
DK (1) DK1797127T3 (en)
EA (1) EA011879B1 (en)
ES (1) ES2629397T3 (en)
IL (1) IL182139A (en)
MA (1) MA28989B1 (en)
MX (1) MX2007003320A (en)
SI (1) SI1797127T1 (en)
WO (1) WO2006036834A2 (en)
ZA (1) ZA200702222B (en)

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