Fusion proteins comprising enzyme replacement therapy enzymes
AssigneeDenali Therapeutics Inc.
InventorsGiuseppe Astarita, Mark S. Dennis, Jennifer A. Getz, Anastasia Henry, Mihalis Kariolis, Cathal Mahon, Adam P. Silverman, Ankita Srivastava, Julie Ullman, Junhua Wang, Joy Yu Zuchero
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Abstract
Provided herein are fusion proteins that comprise an enzyme replacement therapy enzyme and an Fc region, as well as methods of using such proteins to treat a lysosomal storage disorder. Methods for transporting agents across the blood-brain barrier are also provided herein.
Claims68
(canceled)
A protein comprising:
- (a) a first Fc polypeptide that is linked to an enzyme replacement therapy (ERT) enzyme, an ERT enzyme variant, or a catalytically active fragment thereof;
- and
- (b) a second Fc polypeptide that forms an Fc dimer with the first Fc polypeptide,
- wherein the first Fc polypeptide and/or the second Fc polypeptide does not include an immunoglobulin heavy and/or light chain variable region sequence or an antigen-binding portion thereof.
A protein comprising:
- (a) a first Fc polypeptide that is linked to an iduronate 2-sulfatase (IDS), an IDS variant, or a catalytically active fragment thereof;
- and
- (b) a second Fc polypeptide that forms an Fc dimer with the first Fc polypeptide,
- wherein the first Fc polypeptide and/or the second Fc polypeptide does not include an immunoglobulin heavy and/or light chain variable region sequence or an antigen-binding portion thereof.
A protein comprising:
- (a) a first Fc polypeptide that is linked to a N-sulfoglucosamine sulfohydrolase (SGSH), an SGSH variant, or a catalytically active fragment;
- and
- (b) a second Fc polypeptide that forms an Fc dimer with the first Fc polypeptide,
- wherein the first Fc polypeptide and/or the second Fc polypeptide does not include an immunoglobulin heavy and/or light chain variable region sequence or an antigen-binding portion thereof.
A protein comprising:
- (a) a first Fc polypeptide that is linked to an acid sphingomyelinase (ASM), an ASM variant, or a catalytically active fragment thereof;
- and
- (b) a second Fc polypeptide that forms an Fc dimer with the first Fc polypeptide,
- wherein the first Fc polypeptide and/or the second Fc polypeptide does not include an immunoglobulin heavy and/or light chain variable region sequence or an antigen-binding portion thereof.
A protein comprising:
- (a) a first Fc polypeptide that is linked to a β-glucocerebrosidase (GBA), a GBA variant, or a catalytically active fragment thereof;
- and
- (b) a second Fc polypeptide that forms an Fc dimer with the first Fc polypeptide,
- wherein the first Fc polypeptide and/or the second Fc polypeptide does not include an immunoglobulin heavy and/or light chain variable region sequence or an antigen-binding portion thereof.
A polypeptide comprising an Fc polypeptide that is linked to an ERT enzyme, an ERT enzyme variant, or a catalytically active fragment thereof, wherein the Fc polypeptide contains one or more modifications that promote its heterodimerization to another Fc polypeptide.
A method for transporting an agent across the BBB of a mammal, comprising exposing the BBB to a protein that binds to a TfR with an affinity of from about 50 nM to about 250 nM, wherein the protein is linked to the agent and transports the linked agent across the BBB.
A method for treating a lysosomal storage disorder (LSD), comprising administering to a mammal a protein that binds to a TfR with an affinity of from about 50 nM to about 250 nM, wherein the protein is linked to an agent for treating the LSD, thereby exposing the brain of the mammal to the agent.
Dependencies are inferred from the claim text.