Cycling lysosomal targeting antibody conjugates
AssigneeLycia Therapeutics, Inc.
InventorsNicholas Lind, Tao Chen, Christos Kougentakis, Jason G. Lewis, Matthew Shurtleff, Steven Staben, Eric D. Turtle, Richard Yau, Shuai Zheng, Thomas-Toan Tran
Life of this patent
Estimating the term…
Abstract
The present disclosure provides conjugates comprising a moiety that targets a lysosomal targeting molecule, a linker, and an antibody that specifically binds a cell surface target molecule or extracellular target molecule that is targeted for degradation.
Claims63
A conjugate that comprises a ligand moiety, X, conjugated via a linker, L, to a target-binding moiety, Y,
- wherein
- the ligand moiety, X, binds a lysosomal targeting molecule extracellularly;
- the target-binding moiety, Y, binds a target molecule extracellularly,
- the target-binding moiety, Y, dissociates from the target molecule intraendosomally;
- and
- the conjugate is externalized from a cell.
The conjugate of any preceding claim, wherein the conjugate is of formula (I′):
- or a prodrug thereof, or a or a pharmaceutically acceptable salt thereof,
- wherein:
- n is 1 to 500;
- m is 1 to 20;
- X is the ligand moiety;
- and
- Y is the target-binding moiety.
The conjugate of any preceding claim, wherein the lysosomal targeting molecule is a cell surface receptor that provides for internalization of the conjugate.
The conjugate of any preceding claim, wherein the lysosomal targeting molecule is selected from asialoglycoprotein receptor (ASGPR), cation independent mannose-6-phosphate receptor (CI-M6PR also referred to herein as M6PR), folate receptor, LDLR, CD63, sortilin, IFITM3, molecules in the endosome/lysosome pathway, LIMP-1, and LIMP-2.
The conjugate of any preceding claim, wherein X is a moiety that binds ASGPR or M6PR.
The conjugate of any preceding claim, wherein X is a moiety that binds ASGPR.
The conjugate of any one of claims 45-47, wherein X is:
- wherein Ra, Rb, Rc and Rd are independently H or F.
The conjugate of any preceding claim, wherein L comprises of 10 to 60 consecutive branched or linear chain atoms.
The conjugate of any preceding claim, wherein L is of formula (IIb′):
- wherein:
- n is 1, 2, or 3;
- each L1 to L6 is independently a linking moiety which together provide a linear or branched linker between Z1 and Y;
- a, b, c, d, and e are each independently 1, 2, 3, 4, or 5;
- ** represents the point of attachment to L1 of X via Z1;
- and
- *** represents the point of attachment to Y.
A method of degrading a target molecule in a subject in need thereof, comprising administering an effective amount of a conjugate of any preceding claim to the subject.
A method of degrading a target molecule in a subject in need thereof, comprising administering an effective amount of a conjugate that comprises:
- a means for binding a lysosomal targeting molecule extracellularly;
- a means for binding a target molecule extracellularly;
- a means for dissociating from the target molecule intraendosomally;
- and
- wherein the conjugate is externalized from a cell.
Dependencies are inferred from the claim text.