Anti-IgE Antibodies for Cell-Bound IgE Dissociation Without Activation
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing anti-IgE therapeutics face issues such as spontaneous activation of immune cells, suboptimal stability, atypical sequence requirements, and increased propensity for post-translational modification, limiting their therapeutic potential in dissociating IgE from cells.
Innovation Solution
Development of antibodies and antibody fragments that bind cell-bound IgE, dissociate IgE from FcεRI on mast cells and basophils with favorable kinetics, are thermally and chemically stable, and lack DG motifs and methionine residues in their CDRs, thereby preventing cell activation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing anti-IgE therapeutics are used to block IgE, then IgE receptor interactions are blocked, but spontaneous activation of immune cells occurs
Solution Approach 1:
The patent applies local quality by designing the antibody to have different functional properties at different binding sites: the variable region binds IgE with high affinity to block receptor interactions, while the constant region is engineered to avoid crosslinking FcεRI receptors. This spatial differentiation of function allows the antibody to block IgE activity without triggering cell activation, resolving the contradiction between blocking efficacy and harmful activation effects
Solution Approach 2:
The patent uses an intermediary approach by introducing a specially designed anti-IgE antibody that acts as a mediator between IgE and the immune system. This intermediary antibody blocks the pathological interactions between IgE and FcεRI without directly activating the receptor complex, thereby preventing both allergic responses and spontaneous cell activation. The intermediary antibody essentially decouples the blocking function from the activating function
2Reliability
If existing anti-IgE therapeutics are used to dissociate IgE from cells, then IgE blockade is achieved, but suboptimal stability is exhibited
Solution Approach 1:
The patent applies parameter changes by modifying the antibody's amino acid sequence, specifically optimizing the constant region composition and removing destabilizing residues. These parameter changes in the molecular structure enhance the antibody's resistance to thermal and chemical degradation while preserving its ability to bind IgE and block receptor interactions, thus resolving the contradiction between blocking efficacy and stability
3Reliability
If existing anti-IgE therapeutics are used to target IgE dissociation, then IgE dissociation from cells is achieved, but atypical sequence requirements are needed
Solution Approach 1:
The patent applies the taking out principle by extracting and removing the problematic DG motif and methionine residues from the antibody sequence that cause atypical requirements and post-translational modifications. By eliminating these specific sequence elements while retaining the core IgE-binding and dissociation functionality, the patent simplifies the sequence requirements and improves manufacturability without sacrificing therapeutic efficacy
4Reliability
If existing anti-IgE therapeutics are used to block IgE, then receptor interactions are blocked, but increased propensity for post-translational modification occurs
Solution Approach 1:
The patent applies the taking out principle by specifically removing methionine residues and DG motifs from the antibody sequence that are prone to post-translational modifications. This extraction of problematic sequence elements reduces the propensity for oxidation and other modifications, simplifying the manufacturing process and improving batch-to-batch consistency while maintaining the antibody's ability to block IgE receptor interactions
Data Source
AI summary
Provided and exemplified herein are antibodies and antibody fragments that bind an IgE constant domain.