Leptin Antagonist Mutations for Binding Affinity and Immunogenicity
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Solution Overview
Problem
Current leptin antagonists require high doses to achieve efficient binding to the leptin receptor, limiting their therapeutic efficacy and increasing the risk of immunogenicity due to multiple mutations, which can induce neutralizing antibodies.
Innovation Solution
Introduction of specific mutations, such as substituting aspartic acid at position 23 with leucine and threonine at position 12 with isoleucine, to enhance the binding affinity of leptin antagonists to the leptin receptor, reducing the need for high doses and minimizing immunogenicity by using fewer mutations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If multiple amino acid substitutions are introduced to increase binding affinity, then the affinity of leptin antagonist to leptin receptor is improved, but the immunogenicity increases due to induction of neutralizing antibodies
Solution Approach 1:
The patent applies parameter changes by systematically varying the number and position of amino acid substitutions (comparing single, double, and triple mutants) to optimize the balance between binding affinity and immunogenicity. The D23L substitution alone provides sufficient affinity improvement without triggering neutralizing antibodies, while additional substitutions (T12I, L39A) further enhance affinity but increase immunogenicity risk.
Solution Approach 2:
The patent applies local quality by focusing mutations specifically on the hydrophobic binding site (positions 12, 23, and 39) that directly contacts the leptin receptor. This localized approach ensures that mutations are concentrated where they provide maximum functional benefit while minimizing unnecessary changes elsewhere in the molecule that could contribute to immunogenicity.
2Reliability
If high doses of leptin antagonists are administered to achieve efficient binding, then the therapeutic efficacy is improved, but the risk of immunogenicity and side effects increases
Solution Approach 1:
The patent uses parameter changes to achieve a 50-fold increase in binding affinity through specific amino acid substitutions, which directly translates to the ability to achieve therapeutic efficacy at lower doses. The D23L substitution alone provides a 9-fold potency increase in vivo, and combining it with T12I and L39A achieves up to 27-fold potency increase, allowing dose reduction while maintaining therapeutic effect.
3Object-affected harmful factors
If fewer amino acid substitutions are used to reduce immunogenicity, then the safety is improved, but the binding affinity and potency decrease
Solution Approach 1:
The patent applies parameter changes by identifying that a single substitution (D23L) provides a 9-fold potency increase in vivo, which is already therapeutically significant. This allows the use of fewer mutations compared to prior art, reducing immunogenicity while still achieving substantial affinity improvement. The patent demonstrates that additional substitutions (T12I, L39A) can be added incrementally if higher affinity is needed, providing flexibility in optimizing the affinity-safety balance.
Data Source
AI summary
Leptin muteins, in particular leptin antagonists, with increased binding affinity to leptin receptor are provided. These compounds as well as pharmaceutical composition comprising them are useful for the treatment of any disorder in which a non-desirable or deleterious activity of endogenous leptin or an altered innate immune response is implicated.