Truncated Klotho KL1 Polypeptides for High-Yield Antitumor Therapy
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Solution Overview
Problem
Current methods for large-scale production of recombinant klotho proteins, including soluble forms such as KL1, are inadequate for clinical use, and alternative approaches like small molecule up-regulators have not been successful, posing a need for improved therapeutic modalities with potent anti-tumor activity.
Innovation Solution
Development of truncated KL1 domain polypeptides, specifically 340 aa in length, which retain tumor suppressor activity despite structural perturbations, enabling high-yield production in recombinant systems.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If full-length klotho protein or soluble forms (KL1, KL2) are produced recombinantly, then tumor suppressor activity is maintained, but production yield is insufficient for clinical use
Solution Approach 1:
The patent extracts and removes the C-terminal portion (amino acids 341-1012) of the klotho protein, retaining only the N-terminal 340 amino acids. This extraction of the problematic C-terminal region enables high-yield recombinant production while the retained N-terminal region maintains tumor suppressor activity through inhibition of Wnt signaling pathway
Solution Approach 2:
The patent segments the full-length klotho protein into two functional regions: the N-terminal 340 amino acids (retained for activity) and the C-terminal portion (removed for production feasibility). This segmentation allows independent optimization of both production yield and biological function
2Quantity of substance
If small molecule up-regulators are used to increase klotho expression, then klotho levels are increased, but toxicity occurs
Solution Approach 1:
The patent uses a recombinant protein product (truncated klotho) that can be produced in high yields through standard recombinant expression systems, replacing the need for toxic small molecule up-regulators. The protein is produced in host cells, purified, and administered directly as the active therapeutic agent
Solution Approach 2:
The patent changes the approach from small molecule chemistry to protein-based therapy by modifying the molecular weight, structure, and production method. The truncated klotho protein (340 aa) is engineered for high-yield production while maintaining biological activity, eliminating the toxicity associated with small molecule up-regulators
3Productivity
If recombinant klotho production is scaled up, then availability for clinical use increases, but production consistency and quality control become difficult
Solution Approach 1:
The patent removes the C-terminal portion (amino acids 341-1012) that causes production problems, retaining only the N-terminal 340 amino acids. This extraction simplifies the protein structure for recombinant production, enabling consistent high-yield manufacturing while maintaining tumor suppressor activity
Solution Approach 2:
The patent modifies the protein parameters (length, structure, stability) by creating a truncated version that is optimized for recombinant production. The 340 amino acid length and modified structure enable consistent production in host cells while maintaining biological function
Data Source
AI summary
Compositions and methods for treating cancer and inhibiting tumor development are provided. More specifically, provided in embodiments of the invention are novel klotho-derived recombinant polypeptides exhibiting tumor suppressor activity, characterized by a distinct structure and improved properties compared to hitherto known klotho polypeptides.