Antigen-Binding Protein Constructs with pH-Responsive Dissociation
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Solution Overview
Problem
Current antibody-drug conjugates face limitations in achieving enhanced cytostatic or cytotoxic effects and improved endolysosomal delivery, particularly in targeting CD123-expressing cells.
Innovation Solution
Development of antigen-binding protein constructs (ABPCs) with specific antigen-binding domains that have altered dissociation rates and constants at different pH levels, enabling faster binding and degradation within target cells, and conjugation with toxins or drugs for enhanced cell killing and delivery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antibody-drug conjugates are used, then they can bind to CD123 on target cells, but they achieve limited cytostatic/cytotoxic effects and poor endolysosomal delivery
Solution Approach 1:
The patent modifies the pH-dependent dissociation kinetics of the antigen-binding domain as a key parameter. By engineering the binding domain to have faster dissociation at acidic pH (4.0-6.5) compared to neutral pH (7.0-8.0), the conjugate achieves enhanced endolysosomal delivery while maintaining stable binding to CD123 on cell surfaces, thereby resolving the contradiction between delivery efficiency and cytotoxic effect
2Stability of the object's composition
If the antigen-binding domain has high affinity binding, then it maintains stable binding to CD123, but it slows dissociation rate needed for toxin liberation
Solution Approach 1:
The patent creates a dynamic binding system where the antigen-binding domain exhibits pH-responsive dissociation kinetics. The binding interaction is stable at neutral pH for cellular uptake but rapidly dissociates at acidic pH within endolysosomes, enabling timely toxin liberation. This dynamic behavior resolves the contradiction between binding stability and dissociation speed
3Productivity
If the ABPC is designed for rapid internalization, then endolysosomal delivery improves, but CD123 expression on cell surface may increase
Solution Approach 1:
The patent extracts the CD123 antigen from the cell surface through rapid internalization mediated by the engineered antigen-binding domain. The pH-dependent dissociation mechanism ensures that once internalized, the CD123 binding interaction is disrupted and the conjugate is released into the endolysosomal system, preventing re-accumulation on the cell surface and maintaining low CD123 expression levels
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, while maintaining or reducing CD123 expression on the cell surface, effectively addressing the limitations of existing antibody-drug conjugates.
Implementation Method 1
a first antigen-binding domain that is capable of specifically binding CD123 or an epitope of CD123 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
Implementation Method 4
an increase in toxin liberation in the target mammalian cell as compared to a composition including the same amount of a control ABPC
Data Source
AI summary
Provided herein are antigen-binding protein constructs and uses of the same.