Modified Fc molecules
First Claim
1. A composition of matter of the formula
(X1)a—
- F1—
(X2)band multimers thereof, wherein;
F1 is an IgG1 Fc domain comprising SEQ ID NO;
599 modified so that it comprises at least one X3 inserted into or replacing all or part of a sequence selected from SEQ ID NOS;
621, 622, 624, 625, 627, 628, 630, 632, 634, and 636 within a loop region of the IgG1 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)r-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)r-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.
1 Assignment
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Accused Products
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.
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Citations
14 Claims
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1. A composition of matter of the formula
(X1)a—- F1—
(X2)band multimers thereof, wherein; F1 is an IgG1 Fc domain comprising SEQ ID NO;
599 modified so that it comprises at least one X3 inserted into or replacing all or part of a sequence selected from SEQ ID NOS;
621, 622, 624, 625, 627, 628, 630, 632, 634, and 636 within a loop region of the IgG1 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)r-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)r-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. - View Dependent Claims (2, 3, 4, 5, 6, 7)
- F1—
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8. A modified antibody, comprising an Fc domain, F1, wherein:
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F1 is an IgG1 Fc domain comprising SEQ ID NO;
599 modified so that it comprises at least one X3 inserted into or replacing all or part of a sequence selected from SEQ ID NOS;
621, 622, 624, 625, 627, 628, 630, 632, 634, and 636 within a loop region of the IgG1 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. - View Dependent Claims (9, 10, 11, 12, 13, 14)
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Specification