pH-Dependent Antigen-Binding Protein Constructs for DLL3 Targeting
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Solution Overview
Problem
Current antibody-drug conjugates face limitations in achieving enhanced cytostatic or cytotoxic effects on target mammalian cells, particularly in terms of toxin liberation, cell killing, and endolysosomal delivery.
Innovation Solution
Development of antigen-binding protein constructs (ABPCs) with specific antigen-binding domains that have faster dissociation rates or higher dissociation constants at acidic pH, allowing for increased toxin liberation and cell killing, and enhanced endolysosomal delivery by binding to DLL3 epitopes on target cells, including conjugated toxins or drugs.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antibody-drug conjugates are used, then basic cytostatic or cytotoxic effects are achieved, but enhanced toxin liberation, cell killing, and endolysosomal delivery are not achieved
Solution Approach 1:
The patent applies parameter changes by modifying the dissociation characteristics of the antigen-binding domain in response to pH changes. The engineered antibody exhibits pH-dependent dissociation behavior, with faster dissociation rates at acidic pH (4.0-6.5) compared to neutral pH (7.0-8.0), enabling enhanced toxin liberation in the acidic environment of endolysosomes while maintaining stable binding during circulation
Solution Approach 2:
The invention implements dynamics by creating an antigen-binding domain with dynamic dissociation properties that adapt to environmental pH conditions. The antibody dynamically adjusts its binding stability - maintaining tight binding at physiological pH for circulation stability while rapidly dissociating at acidic pH to release toxin payload, transforming a static binding interaction into a dynamic, environment-responsive system
2Stability of the object's composition
If conventional antibody-drug conjugates are used, then circulation stability is maintained, but enhanced endolysosomal delivery and cell killing are not achieved
Solution Approach 1:
The patent employs parameter changes by engineering the antigen-binding domain to exhibit pH-dependent dissociation characteristics. The dissociation constant (KD) and dissociation rate are modified to be pH-responsive, allowing the antibody to maintain stable binding at neutral pH during circulation while achieving rapid dissociation and enhanced toxin delivery at acidic pH within endolysosomes
Solution Approach 2:
The invention uses pH as an intermediary parameter to mediate between circulation stability and endolysosomal delivery efficiency. The pH-dependent dissociation behavior acts as a molecular switch that is triggered by the pH environment, allowing the same antibody construct to exhibit different functional states - stable binding in blood circulation versus rapid dissociation and toxin release in the acidic endolysosomal compartment
3Productivity
If antigen-binding domains with fast dissociation at acidic pH are engineered, then toxin liberation and cell killing are enhanced, but binding stability during circulation may be compromised
Solution Approach 1:
The patent applies local quality by creating spatially differentiated binding characteristics - the antigen-binding domain maintains high binding stability (low dissociation rate) at neutral pH in the circulation environment while exhibiting fast dissociation at acidic pH in the endolysosomal environment. This local differentiation of binding properties allows the same molecular structure to optimize for both circulation stability and toxin release at different locations
Solution Approach 2:
The invention implements dynamics by engineering the antigen-binding domain to dynamically adjust its dissociation rate based on pH conditions. The binding interaction is not static but transitions between stable and labile states in response to environmental pH, enabling the antibody to maintain circulation stability while facilitating efficient toxin liberation in the acidic endolysosomal compartment
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 ABPCs demonstrate increased toxin liberation, target cell killing, and endolysosomal delivery compared to control compositions, providing improved therapeutic efficacy against cancer cells expressing DLL3.
Implementation Method 1
a first antigen-binding domain that is capable of specifically binding DLL3 or an epitope of DLL3 presented on the surface of a target mammalian cell
Implementation Method 2
the dissociation rate of the first antigen-binding domain at a pH of about 4.0 to about 6.5 is faster than the dissociation rate at a pH of about 7.0 to about 8.0
Implementation Method 3
the ABPC is degraded in the target mammalian cell following internalization of the ABPC by the target mammalian cell
Data Source
AI summary
Provided herein are antigen-binding protein constructs capable of specifically binding DLL3 or an epitope of DLL3 presented on the surface of a target mammalian cell, wherein said antigen binding is pH-dependent. Provided are also uses of said antigen-binding protein constructs.