Anti-IL-33 Monoclonal Antibody Epitope Binding With Low Antigenicity
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Solution Overview
Problem
Existing anti-IL-33 monoclonal antibodies face challenges in identifying epitopes consisting of continuous amino acid sequences, leading to reduced efficacy and increased antigenicity when administered to humans, due to mutations in framework regions during production processes.
Innovation Solution
Development of a human anti-IL-33 neutralizing monoclonal antibody that binds to specific epitopes spanning positions 101 to 154 or 199 to 270 of IL-33, with mutations only in complementarity-determining regions, maintaining framework regions from human germline sequences to reduce antigenicity and enhance binding.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing anti-IL-33 monoclonal antibodies are produced using conventional methods, then antibody production is achieved, but mutations occur in framework regions leading to increased antigenicity and reduced efficacy
Solution Approach 1:
The patent applies parameter changes by carefully controlling the amino acid sequence parameters of the antibody framework regions to match human germline sequences exactly, while allowing changes only in the complementarity-determining regions. This selective parameter control reduces antigenicity while maintaining binding efficacy to IL-33.
Solution Approach 2:
The patent applies local quality by differentiating the requirements between different regions of the antibody molecule: framework regions must maintain human germline sequences to minimize antigenicity, while complementarity-determining regions can be mutated to optimize IL-33 binding. This localized optimization resolves the contradiction between efficacy and antigenicity.
2Reliability
If antibodies bind to epitopes in cleaved IL-33 fragments, then binding occurs, but continuous amino acid sequence epitopes are harder to identify and bind to
Solution Approach 1:
The patent applies preliminary action by using recombinant IL-33 protein expressing continuous amino acid sequences (residues 101-154 or 199-270) as immunogens before actual therapeutic use. This preliminary immunization with intact sequence epitopes ensures the antibodies are raised against continuous sequences that remain recognizable even when IL-33 is cleaved in vivo.
Solution Approach 2:
The patent uses synthetic peptides as copies or representations of the continuous amino acid sequence epitopes from full-length IL-33. These peptide copies (e.g., residues 111-130, 131-150, 231-250, or 251-270) serve as simplified immunogens that preserve the continuous sequence epitope structure needed for reliable antibody binding.
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 antibody effectively neutralizes IL-33 by binding to continuous amino acid sequences, reducing human anti-human immunoglobulin antibody responses and providing prolonged in vivo efficacy.
Implementation Method 1
a monoclonal antibody that is capable of binding to an epitope consisting of a continuous amino acid sequence included in positions 101 to 154 or 199 to 270 of SEQ ID NO:226 in the Sequence Listing
Implementation Method 2
a human anti-IL-33 neutralizing monoclonal antibody
Data Source
AI summary
An antibody has an antagonistic effect against IL-33. An isolated human anti-IL-33 neutralizing monoclonal antibody has framework regions with amino acid sequences from a germline, including combinations and fragments of such sequences. The epitopes for a plurality of anti-IL-33 monoclonal antibodies were identified, human anti-IL-33 neutralizing monoclonal antibodies were obtained, and the complementarity-determining regions that achieve high binding ability to IL-33 was specified by introducing mutations in the complementarity-determining regions. The identified complementarity-determining regions were used to produce the foregoing human anti-IL-33 neutralizing monoclonal antibodies having framework regions.