Site-Specific ADC Linkers for Stable High-DAR Antibody Conjugation
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Solution Overview
Problem
Current antibody-drug conjugates (ADCs) face challenges such as non-selective conjugation leading to diverse drug-to-antibody ratios (DAR), reduced circulation half-life, increased off-target toxicity, and batch-to-batch inconsistency, limiting the therapeutic efficacy and safety of cancer treatments.
Innovation Solution
Development of novel disulfur bridge linkers that selectively rebridge pairs of reduced inter-chain disulfide bonds on antibodies, allowing for higher drug loading (DAR ≥4) and stabilization through reformation of disulfide bonds, using linkers with 2,3-disubstituted succinic, fumaric, or maleic groups to covalently cross-link cytotoxic agents to specific sites, minimizing payload loss and enhancing stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If non-selective conjugation of cytotoxic drugs to antibody is used, then drug loading can be achieved, but diverse drug-to-antibody ratios (DAR) result leading to reduced manufacturing precision
Solution Approach 1:
The patent applies local quality by targeting specific local sites on the antibody molecule (inter-chain disulfide bonds in the hinge region) for conjugation, rather than random conjugation throughout the antibody. This localized approach at specific chemical sites ensures consistent DAR while maintaining high drug loading capacity.
Solution Approach 2:
The patent uses an intermediary approach by introducing a linker molecule that mediates between the cytotoxic drug and the antibody's disulfide bonds. This linker system enables controlled conjugation at specific sites, achieving both high drug loading and consistent DAR distribution.
2Ease of manufacture
If non-selective conjugation methods are used, then conjugation can be achieved, but circulation half-life is reduced due to diverse DAR distributions
Solution Approach 1:
The patent changes the chemical parameters of the conjugation process by using disulfide bond-based linkers that form stable cross-links specific to the hinge region disulfide bonds. This parameter change in the conjugation chemistry results in homogeneous DAR distributions that prolong circulation half-life while maintaining ease of manufacture.
3Productivity
If non-selective conjugation is used, then drug delivery can be achieved, but off-target toxicity increases due to heterogeneous ADC populations
Solution Approach 1:
The patent achieves homogeneity by ensuring all antibody molecules undergo conjugation at the same specific sites (inter-chain disulfide bonds), creating a homogeneous ADC population with uniform DAR. This homogeneity eliminates the heterogeneous subpopulations that cause off-target toxicity while maintaining efficient drug delivery.
4Ease of manufacture
If conventional conjugation linkers are used, then conjugation can be achieved, but payload loss occurs reducing therapeutic efficacy
Solution Approach 1:
The patent employs a cyclic cross-linking architecture formed by the linker reacting with disulfide bonds to create a stable cross-linked structure. This cyclic configuration (resembling spheroidality) prevents payload loss by creating a stable, constrained structure that resists degradation, while maintaining conjugation feasibility.
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 novel linkers result in more stable, homogeneous ADCs with prolonged circulation half-life, improved therapeutic index, and reduced off-target toxicity, enabling effective targeted delivery of cytotoxic agents to cancer cells.
Implementation Method 1
linkers... to link a drug and/or a function molecule to a cell-binding agent... covalently cross-linking the pairs of reduced disulfur atoms
Implementation Method 2
selectively rebridge pairs of reduced inter-chain disulfide bonds on antibodies... stabilization through reformation of disulfide bonds
Data Source
AI summary
The present invention relates to novel linkers containing a 2,3-disubstituted succinic group, or 2-monosubstituted, or 2,3-disubstituted fumaric or maleic (trans (E)- or cis (Z)-butenedioic), or acetylenedicarboxyl group for conjugation of a cytotoxic agent, and/or one or more different functional molecules per linker to a cell-binding molecule, through bridge linking pairs of thiols on the cell-binding molecule specifically. The invention also relates to methods of making such linkers, and of using such linkers in making homogeneous conjugates, as well as of application of the conjugates in treatment of cancers, infections and autoimmune disorders.