Antibody-Exatecan Conjugates via Cleavable Peptide-PABC Linker
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Solution Overview
Problem
Current antibody-drug conjugates (ADCs) face challenges with exatecan-based ADCs due to aggregation propensity and poor cell membrane permeability, leading to reduced potency and efficacy, particularly with the direct attachment of GGFG linkers to exatecan, which results in incomplete proteolytic removal and mixed cytotoxic activity profiles.
Innovation Solution
Development of a cleavable peptide-PABC system for metal-free click or thiol conjugation of exatecan to antibodies, minimizing aggregation and enhancing in vivo efficacy by using a linker-drug construct that facilitates specific release of exatecan as a potent cytotoxic payload.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If GGFG linkers are directly attached to exatecan, then conjugation efficiency is improved, but aggregation propensity increases and cell membrane permeability decreases
Solution Approach 1:
The patent introduces a PABC (para-aminobenzyloxycarbonyl) self-immolative linker as an intermediary between the GGFG cleavable linker and the exatecan payload. This intermediary component enables efficient conjugation to the antibody while preventing direct aggregation of exatecan molecules. The PABC group acts as a spacer and self-destructs after proteolytic cleavage of the GGFG linker, facilitating payload release without causing aggregation during circulation.
Solution Approach 2:
The linker construct is segmented into distinct functional modules: the GGFG cleavable linker portion for antigen-dependent release, and the PABC self-immolative portion that prevents aggregation. This segmentation allows each component to perform its specific function independently, resolving the contradiction between conjugation efficiency and aggregation propensity.
2Ease of manufacture
If GGFG linkers are directly attached to exatecan, then conjugation efficiency is improved, but cell membrane permeability decreases
Solution Approach 1:
The PABC self-immolative linker serves as a mediator that prevents the hydrophobic exatecan payload from directly interacting with cell membranes in an aggregating manner. By spacing the payload from the antibody and providing a controlled release mechanism, the PABC group enables effective cell membrane permeation of the released payload without the harmful aggregation effect.
3Reliability
If exatecan is released from ADC, then cytotoxic potency is improved, but aggregation occurs reducing efficacy
Solution Approach 1:
The PABC linker performs self-service by automatically undergoing spontaneous decomposition after proteolytic cleavage of the GGFG linker. This self-immolative property ensures that the exatecan payload is released in its active, non-aggregated form, maintaining cytotoxic potency while preventing aggregation that would reduce efficacy.
Solution Approach 2:
The PABC group acts as a temporary intermediary carrier that holds the exatecan payload in a stable, non-aggregated state during circulation. Upon enzymatic cleavage, the PABC group self-destructs, releasing the payload without causing aggregation, thus preserving both potency and stability.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The resulting antibody-exatecan conjugates exhibit significant in vivo efficacy comparable to the most potent antibody-camptothecin conjugates, with negligible aggregation, demonstrating improved therapeutic potential for cancer treatment.
Implementation Method 1
The cleavable linker may contain a self-immolative unit, for example based on a para-aminobenzenol group and derivatives thereof
Implementation Method 2
The cleavable linker may contain a self-immolative unit, for example based on a para-aminobenzenol group and derivatives thereof
Data Source
AI summary
The present invention concerns an antibody-drug conjugate, having structure (1)wherein AB is an antibody; L1 and L2 are linkers; w is 0 or 1; Z is a connecting group obtained by a metal-free click reaction or by thiol ligation; each R17 is individually an amino acid side chain; n is an integer in the range of 1-5; A is a 5- or 6-membered aromatic or heteroaromatic ring; x is an integer in the range of 1-8; R21 is selected from H, R22, C(O)OH and C(O)R22, wherein R22 is C1-C24 (hetero)alkyl groups, C3-C10 (hetero)cycloalkyl groups, C2-C10 (hetero)aryl groups, C3-C10 alkyl(hetero)aryl groups and C3-C10 (hetero)arylalkyl groups, which optionally substituted and optionally interrupted by one or more heteroatoms selected from O, S and NR23 wherein R23 is independently selected from the group consisting of hydrogen and C1-C4 alkyl groups.