Methods of treating cancer with low density lipoprotein-related protein 6 (LRP6)—half life extender constructs
AssigneeNovartis AG
InventorsDavid Jenkins, Ming Lei, Andreas Loew, Li Zhou
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Abstract
The present invention relates to LRP6 constructs that bind to LRP6 receptor. The LRP6 constructs comprise at least one LRP6 binding moiety and a half-life extender molecule such that the LRP6 construct inhibit the Wnt signaling pathway without potentiation of the Wnt signal. The LRP6 constructs also have an increased half-life to provide more time for the therapeutic benefit.
Claims52
A method of treating a disease mediated by a canonical Wnt signaling pathway cancer, comprising the step of administering to a subject in need thereof an effective amount of a composition comprising a low density lipoprotein-related protein 6(LRP6) construct, wherein said LRP6 construct comprises:
- (a) first and second LRP6 single chain Fv molecules (scFvs) or anti-LRP6 antibody fragments thereof that bind to LRP6;
- and
- (b) a half-life extender molecule chosen from a human serum albumin, or a protein that binds to human serum albumin;
- wherein the first and second scFv molecules or fragments thereof are linked to the N- and C-termini of the human serum albumin, wherein the LRP6 construct inhibits a canonical Wnt signal transduction pathway, and wherein the the LRP6 construct displays no significant potentiation of a Wnt signal in the presence of an LRP6 binding protein, and wherein the disease is a cancer;
- and
- wherein:
- (i) the first anti-LRP6 antibody fragment is linked to the N-terminus of the half-life extender molecule and binds to the Propeller 1 region of LRP6, and the second anti-LRP6 antibody fragment is linked to the C-terminus of the half-life extender molecule and binds to the Propeller 3 region of LRP6;
- or
- (ii) the first anti-LRP6 antibody fragment is linked to the C-terminus of the half-life extender molecule and binds to the Propeller 1 region of LRP6, and the second anti-LRP6 antibody fragment is linked to the N-terminus of the half-life extender molecule and binds to the Propeller 3 region of LRP6.
A method of treating a cancer, comprising administering to a subject in need thereof an effective amount of a composition comprising a low density lipoprotein-related protein 6 (LRP6) construct, wherein said LRP6 construct comprises a first antibody or antibody fragment thereof that binds to the Propeller 1 region of LRP6 and a second LRP6 antibody or antibody fragment thereof that binds to the Propeller 3 region of LRP6, said LRP6 construct further comprising a protein that binds to human serum albumin, wherein the LRP6 construct inhibits a canonical Wnt signal transduction pathway, and displays no significant potentiation of a Wnt signal in the presence of an LRP6 binding protein, and
- wherein:
- (i) the first anti-LRP6 antibody or antibody fragment (a) is linked to the N-terminus of the protein that binds to human serum albumin and (b) binds to the Propeller 1 region of LRP6, and the second anti-LRP6 antibody or antibody fragment (c) is linked to the C-terminus of the protein that binds to human serum albumin and (d) binds to the Propeller 3 region of LRP6;
- or
- (ii) the first anti-LRP6 antibody or antibody fragment (a) is linked to the C-terminus of the protein that binds to human serum albumin and (b) binds to the Propeller 1 region of LRP6, and the second anti-LRP6 antibody or antibody fragment (c) is linked to the N-terminus of the protein that binds to human serum albumin and (d) binds to the Propeller 3 region of LRP6.
A method of treating a cancer, comprising administering to a subject in need thereof an effective amount of a composition comprising a low density lipoprotein-related protein 6 (LRP6) construct, wherein said LRP6 construct comprises:
- (a) a biparatopic antibody fragment comprising a first anti-LRP6 antibody fragment and second anti-LRP6 antibody fragment;
- and
- (b) a protein that binds to human serum albumin, wherein the protein that binds to human serum albumin is linked to each of the first antibody fragment and the second antibody fragment by an amino acid attachment linker that comprises alanine, glycine, or serine residues used alone or in combination,
- wherein the LRP6 construct inhibits both Wnt1- and Wnt3-mediated Wnt signal transduction pathways, and displays no significant potentiation of a Wnt signal in the presence of an LRP6 binding protein;
- and
- wherein:
- (i) the first anti-LRP6 antibody fragment is linked to the N-terminus of the protein that binds to human serum albumin and binds to the Propeller 1 region of LRP6, and the second anti-LRP6 antibody fragment is linked to the C-terminus of the protein that binds to human serum albumin and binds to the Propeller 3 region of LRP6;
- or
- (ii) the first anti-LRP6 antibody fragment is linked to the C-terminus of protein that binds to human serum albumin and binds to the Propeller 1 region of LRP6, and the second anti-LRP6 antibody fragment is linked to the N-terminus of the protein that binds to human serum albumin and binds to the Propeller 3 region of LRP6.
Dependencies are inferred from the claim text.