pH-Dependent Anti-PCSK9 Antibody Binding Dynamics
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Solution Overview
Problem
Current monoclonal antibodies, such as IgG1, have limitations in terms of dose frequency and efficacy due to their pH-dependent binding characteristics, particularly at endosomal and physiological pH levels, which affect their half-life and antigen interaction dynamics.
Innovation Solution
Development of antibodies with pH-dependent binding properties, specifically designed to have higher affinity at physiological pH (pH 7.4) compared to endosomal pH (pH 5.5-6.0), allowing for preferential dissociation from antigens in the endosome and optimized half-life, achieved through targeted substitutions and microenvironment modifications in the antibody's variable regions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If antibodies bind strongly to antigens at endosomal pH, then antigen-mediated clearance is enhanced, but antibody half-life is reduced
Solution Approach 1:
The patent applies dynamics by engineering antibodies with pH-dependent binding characteristics that allow the antibody-antigen complex to form at physiological pH (7.4) for clearance, but dissociate at endosomal pH (5.5-6.0) to prevent degradation. This dynamic behavior is achieved through specific amino acid substitutions in the variable region that alter protonation states and binding affinity based on environmental pH
Solution Approach 2:
The patent changes the binding parameter (affinity) as a function of pH by introducing specific substitutions in the antibody variable region. These substitutions create pH-sensitive ionizable groups that modulate the electrostatic interactions between antibody and antigen, enabling strong binding at physiological pH and weak binding at endosomal pH
2Object-affected harmful factors
If therapeutic dose is reduced, then treatment safety is improved, but pharmacodynamic effect may be insufficient
Solution Approach 1:
The patent ensures continuous pharmacodynamic effect by engineering antibodies that resist antigen-mediated clearance through pH-dependent dissociation. The antibodies maintain active circulation by escaping endosomal degradation, providing sustained target engagement and continuous therapeutic effect even at lower doses
Solution Approach 2:
The patent enables antibodies to self-protect from degradation through engineered pH-dependent binding characteristics. The antibodies automatically dissociate from antigens in the acidic endosomal environment, preventing their own degradation and maintaining therapeutic levels without requiring higher dosing
3Duration of action of moving object
If FcRn binding is increased at pH 6.0, then antibody half-life is extended, but binding affinity at physiological pH may be affected
Solution Approach 1:
The patent segments the pH-dependent binding function into two distinct mechanisms: FcRn-mediated recycling in the Fc region and antigen-binding in the variable region. This allows independent optimization of half-life extension through FcRn interactions while maintaining pH-dependent antigen dissociation in the variable region to preserve binding affinity at physiological pH
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
These antibodies exhibit extended half-life and pharmacodynamic effects, reducing antigen-mediated clearance, and enabling lower therapeutic doses by optimizing binding affinity and stability, particularly for targets like PCSK9, IgE, DKK1, and GMCSF receptor.
Implementation Method 1
antibodies with pH dependent binding such that the KD and/or koff ratio at endosomal pH/physiologic pH (e.g., pH 5.5/pH 7.4 or pH 6.0/pH 7.4) is 2 or greater
Data Source
AI summary
The present invention relates to antibodies with pH dependent binding to its antigen such that the affinity for antigen binding at physiological pH (i.e., pH 7.4) is greater than at endosomal pH (i.e., pH 6.0 or 5.5). In other words, the KD or koff ratio at pH 5.5/pH 7.4 or at pH 6.0/pH 7.4 is more than, or ranges between, 2, 3, 4, 8, 10, 16, 20, 30, 40, or 100 or more. Such pH dependent antibodies preferentially dissociate from the antigen in the endosome. This can increase antibody half life, as compared to antibodies with equivalent KDs at pH 7.4 but with no pH dependent binding, when the antigen is one that undergoes antigen-mediated clearance (e.g., PCSK9). Antibodies with pH dependent binding can decrease total antigen half life when the antigen undergoes reduced clearance when bound to antibody (e.g., IL6). Antibodies with pH dependent binding can also prolong the decrease in antigen which is not antibody-bound. This can be important when antagonizing a target antigen typically present at high levels (e.g., IgE, DKK1, C5 and SOST). In addition, such antibodies can increase antigen half life when the antigen is a receptor and the receptor has increased clearance when bound to antibody (e.g., GMCSF receptor).