pH-Dependent Antigen-Binding Protein Constructs for Enhanced Toxin Liberation
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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, facilitating enhanced toxin liberation and cell killing, and increased endolysosomal delivery by targeting CD22 on mammalian cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antibody-drug conjugates are used, then they can deliver cytotoxic agents to target cells, but they fail to achieve enhanced toxin liberation and cell killing efficacy
Solution Approach 1:
The patent modifies the antigen-binding domain to exhibit pH-dependent dissociation characteristics, where the binding affinity changes between physiological pH (7.4) and acidic pH (endolysosomal environment). This parameter change enables the conjugate to maintain stable binding during circulation while facilitating toxin release in the acidic endolysosomal compartment, thereby resolving the contradiction between reliable toxin delivery and enhanced liberation efficacy
Solution Approach 2:
The invention introduces dynamic pH-responsive behavior to the antibody-drug conjugate system. The antigen-binding domain dynamically adjusts its dissociation rate based on environmental pH, remaining tightly bound at physiological pH but dissociating more rapidly in acidic conditions. This dynamic characteristic enables both reliable target cell binding and enhanced toxin liberation, simultaneously improving reliability and productivity
2Reliability
If conventional antibody-drug conjugates are used, then they can bind to target cells, but they show insufficient endolysosomal delivery
Solution Approach 1:
The patent engineering the antigen-binding domain with specific pH-dependent dissociation properties that enhance endolysosomal delivery. The modified domain exhibits faster dissociation at acidic pH compared to physiological pH, which facilitates efficient toxin release within the endolysosomal compartment. This parameter optimization simultaneously improves delivery efficiency and therapeutic efficacy by ensuring the cytotoxic agent is released at the correct intracellular location
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, potentially leading to improved therapeutic efficacy against cancer cells.
Implementation Method 1
a first antigen-binding domain that is capable of specifically binding CD22 or an epitope of CD22 presented on the surface of a target mammalian cell
Implementation Method 2
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 CD22 or an epitope of CD22 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.