Self-stabilizing linker conjugates
AssigneeBeOne Medicines I GmbH
InventorsCharng-Sheng Tsai, Mei-Hsuan Tsai, Xiaodong Wei, Wei Luo, Liming Wu
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Abstract
The present disclosure provides antibody drug conjugate platforms comprising a self-stabilizing linker assembly component, and antibody drug conjugates comprising platform-derived linker-payloads and antibodies or antigen-binding fragments thereof. In some embodiments, an antibody drug conjugate is of the following formula: or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof, wherein values for the variables (e.g., BA, RG, R1a, R1b, r, RS, R2a, R2b, s, R4, R3a, R3b, t, RE, A, a′, W, w′, Y, y′, PA, x) are as described herein.
Claims69
A compound of Formula (I):
- or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof, wherein:
- BA is a binding agent selected from a humanized, chimeric, or human antibody or an antigen binding fragment thereof;
- RG is a reactive group residue;
- RS is an open-ring stabilizing group;
- RE is an open-ring enhancer;
- each of R1a and R1b is, independently, H;
- substituted or unsubstituted C1-4 alkyl;
- substituted or unsubstituted C3-5 cycloalkyl;
- or R1a and R1b together with the atom to which they are attached form a substituted or unsubstituted C3-5 cycloalkyl;
- each of R2a and R2b is, independently, H;
- substituted or unsubstituted C1-4 alkyl;
- substituted or unsubstituted C3-5 cycloalkyl;
- or R2a and R2b together with the atom to which they are attached form a substituted or unsubstituted C3-5 cycloalkyl;
- each of R3a and R3b is, independently, H;
- substituted or unsubstituted C1-4 alkyl;
- substituted or unsubstituted C3-5 cycloalkyl;
- or R3a and R3b together with the atom to which they are attached form a substituted or unsubstituted C3-5 cycloalkyl;
- R4 is H;
- substituted or unsubstituted C1-4 alkyl;
- or substituted or unsubstituted C3-5 cycloalkyl;
- each of r, s, and t is, independently, 0, 1, or 2;
- A is a Stretcher unit residue;
- subscript a′ is 0 or 1;
- W is a Cleavable unit;
- subscript w′ is 0 or 1;
- Y is a Spacer unit;
- subscript y′ is 0 or 1;
- PA is a payload residue;
- and
- subscript x is from 1 to 15.
The compound of claim 0, wherein RS is an amino group.
The compound of any one of claims 1-0, wherein r is 0.
The compound of any one of claims 1-0, wherein s is 1.
The compound of any one of claims 1-0, wherein t is 1 or 2.
The compound of any one of claims 1-0, wherein A
- is —(CH2)n—C(═O)—, —CH2—C(═O)—NH—(CH2)n—C(═O)—, —(CH2CH2O)n—CH2CH2—C(═O)—, —CH [—(CH2)n—COOH]—C(═O)—, —CH2—C(═O)—NH—(CH2)n—C(═O)—NH—(CH2)n—C(═O)—, or —C(═O)—(CH2)n—C(═O)—, wherein each n independently represents an integer of 1, 2, 3, 4, or 5.
The compound of any one of claims 1-0, wherein Ww′ is one of the following formulas:
- and
- wherein HG is a hydrophilic moiety or hydrogen.
A compound of Formula (II):
- or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer, wherein:
- RG is a reactive group;
- RS is an open-ring stabilizing group;
- RE is an open-ring enhancer;
- each of R1a and R1b is, independently, H;
- substituted or unsubstituted C1-4 alkyl;
- substituted or unsubstituted C3-5 cycloalkyl;
- or R1a and R1b together with the atom to which they are attached form a substituted or unsubstituted C3-5 cycloalkyl;
- each of R2a and R2b is, independently, H;
- substituted or unsubstituted C1-4 alkyl;
- substituted or unsubstituted C3-5 cycloalkyl;
- or R2a and R2b together with the atom to which they are attached form a substituted or unsubstituted C3-5 cycloalkyl;
- each of R3a and R3b is, independently, H;
- substituted or unsubstituted C1-4 alkyl;
- substituted or unsubstituted C3-5 cycloalkyl;
- or R3a and R3b together with the atom to which they are attached form a substituted or unsubstituted C3-5 cycloalkyl;
- R4 is H, substituted or unsubstituted C1-4 alkyl;
- or substituted or unsubstituted C3-5 cycloalkyl;
- each of r, s, and t is, independently, 0, 1, or 2;
- A is a Stretcher unit residue;
- subscript a′ is 0 or 1;
- W is a Cleavable unit;
- subscript w′ is 0 or 1;
- Y is a Spacer unit;
- subscript y′ is 0 or 1;
- and
- PA is a payload residue.
The compound of claim 0, wherein RE is —OC(═O)NH—.
A compound of Formula (III):
- or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof,
- wherein:
- RG is a reactive group;
- RS is an open-ring stabilizing group;
- RE is an open-ring enhancer;
- each of R1a and R1b is, independently, H;
- substituted or unsubstituted C1-4 alkyl;
- substituted or unsubstituted C3-5 cycloalkyl;
- or R1a and R1b together with the atom to which they are attached form a substituted or unsubstituted C3-5 cycloalkyl;
- each of R2a and R2b is, independently, H;
- substituted or unsubstituted C1-4 alkyl;
- substituted or unsubstituted C3-5 cycloalkyl;
- or R2a and R2b together with the atom to which they are attached form a substituted or unsubstituted C3-5 cycloalkyl;
- each of R3a and R3b is, independently, H;
- substituted or unsubstituted C1-4 alkyl;
- substituted or unsubstituted C3-5 cycloalkyl;
- or R3a and R3b together with the atom to which they are attached form a substituted or unsubstituted C3-5 cycloalkyl;
- R4 is H;
- substituted or unsubstituted C1-4 alkyl;
- or substituted or unsubstituted C3-5 cycloalkyl;
- each of r, s, and t is, independently, 0, 1, or 2;
- A is a Stretcher unit;
- and
- subscript a′ is 0 or 1.
The compound of claim 0, wherein R7 is OH, NH2, NHCH3, or N(CH3)2.
Dependencies are inferred from the claim text.