Dual transporters and methods of use
AssigneeDenali Therapeutics Inc.
InventorsPadma AKKAPEDDI, Darren CHAN, Gerald Maxwell CHERF, Kylie S. CHEW, Mark S. DENNIS, Mihalis S. KARIOLIS, Arash MOSHKFOROUSH, Robert G. THORNE, Robert C. WELLS, Joy Yu ZUCHERO
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Abstract
Described are dual transporters and methods of making and using the dual transporters. The dual transporters bind to a blood brain barrier transport protein and a second protein that is expressed on the luminal surface of the blood brain barrier or is a brain retention protein. The dual transporters improve delivery to the central nervous system.
Claims161
A dual transporter comprising:
- (a) a first binding region that specifically binds to a blood brain barrier (BBB) transport protein, wherein the BBB transport protein is the transferrin receptor (TfR) or CD98hc;
- and
- (b) a second binding region that specifically binds to a second protein wherein the second protein is expressed on the luminal surface of the BBB or is a brain retention protein, and wherein the second protein is different from the BBB transport protein.
A method of manufacturing a dual transporter comprising:
- (a) providing (i) a first polypeptide comprising a first binding region known to specifically binds to a BBB transport protein and (ii) a second polypeptide comprising a second binding region known to specifically binds a second protein, wherein the second protein is expressed on the luminal surface of the BBB or is a brain retention protein, and wherein the second protein is different from the BBB transport protein;
- and
- (b) forming a single molecule that incorporates the first polypeptide and the second polypeptide, thereby forming the dual transporter;
- wherein the dual transporter has increased and/or prolonged brain exposure in an animal as compared to a corresponding control molecule that binds to only the BBB transport protein or only the second protein.
A method of identifying a dual transporter comprising:
- (a) providing (i) a first polypeptide comprising a first binding region known to specifically binds to a BBB transport protein and (ii) a second polypeptide comprising a second binding region known to specifically binds a second protein, wherein the second protein is expressed on the luminal surface of the BBB or is a brain retention protein, and wherein the second protein is different from the BBB transport protein;
- (b) forming a single molecule that incorporates the first polypeptide and the second polypeptide;
- and
- (c) measuring the brain concentration of the single molecule at a predetermined time and identifying the single molecule as a dual transporter if the single molecule is present in the brain at a higher concentration than a corresponding control molecule that binds only to the BBB transport protein or the second protein.
A method for improving delivery to the central nervous system of a therapeutic agent linked to a delivery vehicle having a first binding region that specially binds to a BBB transport protein, the method comprising linking the delivery vehicle to a second binding region that specifically binds to a second protein wherein the second protein is expressed on the luminal surface of the BBB or is a brain retention protein, and wherein the second protein is different from the BBB transport protein.
A method for improving delivery to the central nervous system of a delivery vehicle having a first binding region the specially binds to a BBB transport protein, the method comprising linking the delivery vehicle to a second binding region that specifically binds to a second protein wherein the second protein is expressed on the luminal surface of the BBB or is a brain retention protein, and wherein the second protein is different from the BBB transport protein.
A method for improving delivery of a therapeutic agent to the central nervous system wherein the therapeutic agent is linked to a polypeptide that specifically binds TfR, the method comprising linking the polypeptide that specifically binds TfR to a second binding region that specifically binds to a second protein wherein the second protein is expressed on the luminal surface of the BBB or is a brain retention protein, and wherein the second protein is not TfR.
A method for improving delivery of a therapeutic agent to the central nervous system wherein the therapeutic agent is linked to a polypeptide that specifically binds CD98hc, the method comprising linking the polypeptide that specifically binds CD98hc to a second binding region that specifically binds to a second protein wherein the second protein is expressed on the luminal surface of the BBB or is a brain retention protein, and wherein the second protein is not CD98hc.
Dependencies are inferred from the claim text.