Humanized KIR3DL2 Antibody Stability Through Targeted Substitutions
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Solution Overview
Problem
Existing antibodies targeting KIR3DL2 receptors have low affinity and stability, leading to ineffective therapeutic applications for conditions like Mycosis Fungoides and Sezary Syndrome, and there is a need for improved antibodies that can inhibit KIR3DL2-HLA B27 dimer interactions without causing receptor internalization.
Innovation Solution
Development of humanized antibodies with specific amino acid substitutions at positions 39 in the heavy chain and 38 in the light chain, utilizing antigen combining regions of antibodies 2B12 and 10G5, which enhance physical stability and affinity, preventing receptor internalization and allowing effective blockade of KIR3DL2-HLA B27 interactions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing antibodies are used to target KIR3DL2 receptors, then therapeutic applications are attempted, but the antibodies have low affinity and stability leading to ineffective treatment
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid substitutions at positions 39 in the heavy chain and 38 in the light chain of the antibody framework. These substitutions modify the physical and chemical parameters of the antibody structure, resulting in enhanced stability and affinity for the KIR3DL2 receptor, thereby resolving the contradiction between therapeutic effectiveness and antibody quality
Solution Approach 2:
The patent applies local quality by making targeted amino acid substitutions at specific positions (39 in heavy chain, 38 in light chain) rather than modifying the entire antibody structure. This localized modification approach improves the critical binding and stability regions while maintaining the overall antibody function and structure
2Reliability
If antibodies block KIR3DL2-HLA B27 interactions, then therapeutic benefit is achieved, but receptor internalization may occur reducing effectiveness
Solution Approach 1:
The patent uses parameter changes through amino acid substitutions that modify the antibody's binding characteristics. These substitutions alter the interaction parameters between the antibody and KIR3DL2 receptor, enabling effective blockade of KIR3DL2-HLA B27 interactions while preventing receptor internalization, thus maintaining receptor stability on the cell surface
Data Source
AI summary
The present invention provides antibodies having improved stability. Included are antibodies that are capable of binding to KIR3DL2 polypeptides. The antibodies are suitable for the treatment of disorders characterized by KIR3DL2-expressing cells, particularly CD4+ T cells, including malignancies such as Mycosis Fungoides and Sezary Syndrome, and KIR3DL2-expressing autoimmune disorders.