Anti-hIL-4Rα Antibody Fast Off-Rate Kinetics
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Solution Overview
Problem
Current anti-hIL-4Rα antibodies have limitations such as variable efficacy, potential for resistance due to continuous administration, and rapid antigen-mediated clearance due to high affinity and low off-rate.
Innovation Solution
Development of a novel anti-hIL-4Rα antibody with a high equilibrium dissociation constant (KD) at a pM level and an epitope different from conventional antibodies, aiming for a faster antigen dissociation rate to reduce clearance in vivo.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current anti-hIL-4Rα antibodies are administered continuously to maintain therapeutic efficacy, then the therapeutic effect is sustained, but resistance develops due to continuous administration
Solution Approach 1:
The patent inverts the conventional approach by designing an antibody with unusually fast off-rate kinetics rather than slow off-rate. This inverted kinetic profile allows the antibody to bind and neutralize IL-4Rα quickly upon binding, then dissociate rapidly to avoid continuous occupation that leads to resistance, thereby maintaining therapeutic efficacy while minimizing resistance development
Solution Approach 2:
The patent changes the kinetic parameters of antibody-antigen binding by optimizing the off-rate to be faster than conventional antibodies. This parameter change in dissociation kinetics allows the antibody to maintain therapeutic effect through rapid binding events while avoiding the continuous presence that triggers resistance mechanisms
2Strength
If the antibody has high affinity binding to hIL-4Rα, then the binding strength is improved, but the antigen-mediated clearance rate increases due to low off-rate
Solution Approach 1:
The patent changes the kinetic parameters by decoupling affinity from off-rate, creating an antibody that achieves high affinity through rapid association while maintaining a fast off-rate. This parameter optimization prevents antigen-mediated clearance by ensuring the antibody does not remain bound indefinitely, allowing it to be recycled and continue therapeutic action
3Duration of action of moving object
If the antibody binds tightly to hIL-4Rα with low off-rate, then the duration of action is extended, but the antigen-mediated clearance occurs rapidly
Solution Approach 1:
The patent inverts the conventional assumption that long duration requires slow off-rate. Instead, it designs an antibody with fast off-rate that achieves sustained therapeutic effect through rapid binding cycles, preventing antigen-mediated clearance by avoiding prolonged complex formation that would trigger immune system elimination
Data Source
AI summary
An antibody or antigen-binding fragment thereof, which binds with a high pM-level affinity to a human IL-4 receptor alpha chain that is a human IL-4 receptor, is provided. The antibody or antigen-binding fragment has a different epitope and a different antigen dissociation rate than existing antibodies. A nucleic acid encoding the antibody or antigen-binding fragment thereof, a vector including the nucleic acid, a cell transformed with the vector, a method for producing the antibody or antigen-binding fragment thereof, a conjugate comprising the antibody or antigen-binding fragment thereof, a composition for preventing or treating inflammatory diseases, and a composition for diagnosing inflammatory diseases are disclosed.