Antigen-Binding LEPR Antibodies for Effective Leptin Signaling Blockade
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Solution Overview
Problem
Existing therapeutic approaches for addressing leptin resistance and related disorders, such as anorexia, cachexia, autoimmune disorders, and cancer, have shown limited efficacy, necessitating alternative methods to down-regulate leptin receptor signaling.
Innovation Solution
Development of antagonist antibodies and antigen-binding fragments that specifically target the human leptin receptor (LEPR), including full-length antibodies like IgG1 or IgG4, and fragments like Fab, F(ab')2, or scFv, with defined CDR sequences, to block or down-regulate leptin receptor signaling.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If leptin receptor peptide antagonists and soluble leptin receptor variants are used to block leptin signaling, then leptin receptor signaling is down-regulated, but therapeutic efficacy remains limited
Solution Approach 1:
The patent applies parameter changes by developing antibodies with optimized binding affinity and specificity parameters. The antibodies exhibit nanomolar to picomolar binding affinities to the leptin receptor, representing a significant improvement in binding strength compared to previous peptide antagonists. This parameter optimization enables more effective signaling blockade and improved therapeutic efficacy
Solution Approach 2:
The invention employs composite materials by creating chimeric, humanized, and fully human antibody molecules that combine different structural elements. These composite antibody structures integrate variable regions from different sources with human constant regions, achieving both high affinity binding and reduced immunogenicity, thereby improving therapeutic efficacy
2Object-affected harmful factors
If competitive LEPR antagonists such as antibody 9F8 are used, then leptin receptor binding is blocked, but therapeutic effectiveness is insufficient
Solution Approach 1:
The patent improves therapeutic effectiveness by optimizing key parameters including binding affinity (achieving nanomolar to picomolar ranges), specificity (reducing cross-reactivity with other cytokine receptors), and pharmacokinetic properties (enhancing stability and half-life). These parameter improvements enable more reliable and effective therapeutic outcomes compared to antibody 9F8
Solution Approach 2:
The invention uses copying by creating multiple antibody variants based on the original 9F8 binding mechanism. These include chimeric versions, humanized versions, and fully human counterparts that replicate and refine the binding properties of 9F8 while eliminating its limitations, thereby achieving superior therapeutic effectiveness
3Ease of operation
If nanobodies targeting leptin receptor are used, then LEPR binding is achieved, but clinical efficacy is limited
Solution Approach 1:
The patent applies merging by combining the advantages of different antibody formats. The resulting antibodies integrate the high binding capability of nanobodies with the enhanced stability, extended half-life, and improved pharmacokinetic properties of full-length IgG molecules. This merging achieves both ease of binding and reliable clinical efficacy
Solution Approach 2:
The invention uses composite materials by creating antibody molecules that combine variable domains with human constant regions. This composite structure preserves the high affinity binding characteristics while adding stability and pharmacokinetic advantages, thereby improving clinical efficacy beyond what nanobodies alone can achieve
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 antibodies effectively down-regulate leptin receptor signaling, providing therapeutic benefits for conditions associated with elevated leptin levels, including anorexia, cachexia, autoimmune disorders, and cancer, by reducing food intake, body weight, and fat mass in animal models.
Implementation Method 1
antibodies and antigen-binding fragments thereof that bind human leptin receptor (LEPR)
Data Source
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AI summary
The present invention provides antibodies and antigen-binding fragments of antibodies that bind to leptin receptor (LEPR), and methods of using the same. According to certain embodiments, the invention includes antibodies and antigen-binding fragments of antibodies that bind LEPR and antagonize LEPR signaling. In certain embodiments, the invention includes antibodies and antigen-binding fragments of antibodies that bind LEPR in the presence or absence of leptin. In other embodiments, the invention includes antibodies and antigen-binding fragments of antibodies that exhibit partial agonism of LEPR signaling. The antibodies and antigen-binding fragments of the present invention are useful for the treatment of various conditions, including but not limited to congestive heart failure cachexia, pulmonary cachexia and cancer cachexia, autoimmune disorders such as inflammatory bowel disease, lupus erythematosus, multiple sclerosis, psoriasis, cardiovascular diseases, elevated blood pressure, neurodegenerative disorders, depression, cancer such as hepatocellular carcinoma, melanoma, breast cancer, and other diseases and disorders associated with or caused by elevated leptin signaling.