Targeted therapeutic proteins
AssigneeSymbiontics, Inc.
InventorsJonathan H. LeBowitz, Stephen M. Beverley
Life of this patent
Estimating the term…
Abstract
Targeted therapeutics that localize to a specific subcellular compartment such as the lysosome are provided. The targeted therapeutics include a therapeutic agent and a targeting moiety that binds a receptor on an exterior surface of the cell, permitting proper subcellular localization of the targeted therapeutic upon internalization of the receptor. Nucleic acids, cells, and methods relating to the practice of the invention are also provided.
Claims57
A targeted therapeutic comprising:
- a therapeutic agent that is therapeutically active in a mammalian lysosome;
- and
- means for binding an extracellular domain of human cation-independent mannose-6-phosphate receptor in a mannose-6-phosphate-independent manner.
A targeted therapeutic comprising:
- a therapeutic agent that is therapeutically active in a mammalian lysosome;
- and
- an unglycosylated lysosomal targeting domain that binds an extracellular domain of human cation-independent mannose-6-phosphate receptor.
A targeted therapeutic comprising:
- a therapeutic agent that is therapeutically active in a human lysosome;
- and
- a lysosomal targeting domain that binds an extracellular domain of human cation-independent mannose-6-phosphate receptor and
- (i) does not bind a mutein in which amino acid 1572 of the human cation-independent mannose-6-phosphate receptor is changed from isoleucine to threonine;
- or
- (ii) binds the mutein with a dissociation constant at least ten times the dissociation constant for binding the extracellular domain of human cation-independent mannose-6-phosphate receptor.
A targeted therapeutic comprising:
- a therapeutic agent that is therapeutically active in a human lysosome;
- and
- a lysosomal targeting domain that is capable of binding a receptor domain consisting essentially of repeats 10-15 of the human cation-independent mannose-6-phosphate receptor.
A targeted therapeutic comprising:
- a therapeutic agent that is therapeutically active in a human lysosome;
- and
- a binding moiety sufficiently duplicative of human IGF-II such that the binding moiety binds the human cation-independent mannose-6-phosphate receptor.
A targeted therapeutic comprising:
- a therapeutic agent that is therapeutically active in a human lysosome;
- and
- a polypeptide comprising the amino acid sequence phenylalanine-arginine-serine.
A targeted therapeutic comprising:
- a therapeutic agent that is therapeutically active in a human lysosome;
- and
- a polypeptide comprising an amino acid sequence at least 75% homologous to amino acids 48-55 of human IGF-II.
A targeted therapeutic comprising:
- a therapeutic agent that is therapeutically active in a human lysosome;
- amino acids 8-28 of human IGF-II;
- and
- amino acids 41-61 of human IGF-II.
A targeted therapeutic comprising:
- a therapeutic agent that is therapeutically active in a human lysosome;
- amino acids 41-61 of human IGF-II;
- and
- a mutein of amino acids 8-28 of human IGF-II, the mutein differing from human IGF-II at a position selected from the group consisting of amino acid 9, amino acid 19, amino acid 26, and amino acid 27.
A therapeutic fusion protein comprising:
- a therapeutic domain and
- a subcellular targeting domain that binds to an extracellular domain of a receptor on an exterior surface of a cell and, upon internalization of the receptor, permits localization of the therapeutic domain to a subcellular compartment where the therapeutic domain is therapeutically active.
A method of treating a patient, the method comprising:
- (i) synthesizing a targeted therapeutic comprising a therapeutic agent that is therapeutically active in a mammalian lysosome and a targeting moiety that binds human cation-independent mannose-6-phosphate receptor in a mannose-6-phosphate-independent manner;
- and
- (ii) administering the targeted therapeutic to the patient.
A method of producing a targeted therapeutic, the method comprising the steps of:
- (a) providing a molecular model defining a three-dimensional shape representative of at least a portion of human IGF-II;
- (b) identifying a candidate IGF-11 analog having a three-dimensional shape corresponding to the three-dimensional shape representative of at least a portion of human IGF-II;
- and
- (c) producing a therapeutic agent directly or indirectly bound to the candidate IGF-II analog, wherein the therapeutic agent is therapeutically active in a mammalian lysosome.
Dependencies are inferred from the claim text.