LRP5-Binding Polypeptides for Selective Wnt Inhibition in Tumors
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Solution Overview
Problem
Current LRP5-binding molecules for treating cancer, such as DKK1, exhibit severe toxicity and are not authorized for therapeutic use due to their undesirable effects on normal tissues, and existing antibodies lack specific binding properties and pharmacokinetic profiles necessary for effective cancer treatment.
Innovation Solution
Development of polypeptides comprising immunoglobulin single variable domains (ISVDs) that specifically bind to LRP5, including humanized VHH domains, with optional albumin binding moieties for extended half-life, to selectively inhibit Wnt signaling pathways in cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If DKK1 is used to inhibit Wnt signaling in cancer cells, then tumor growth is suppressed, but severe toxicity occurs in normal tissues
Solution Approach 1:
The patent applies local quality by creating antibodies with differential binding affinities to LRP5 in different tissue contexts. The antibodies are designed to selectively bind to LRP5 on tumor cells while having reduced binding to LRP5 on normal tissues, thereby achieving localized inhibition of Wnt signaling in tumors while sparing normal tissues from toxicity.
Solution Approach 2:
The patent uses LRP5 as an intermediary target between Wnt ligands and the signaling pathway. By developing antibodies that bind to LRP5, the invention creates a mediator that blocks the interaction between Wnt ligands and LRP5, thereby inhibiting Wnt signaling without directly affecting other pathways in normal tissues.
2Reliability
If conventional antibodies bind to LRP5 to inhibit Wnt signaling, then cancer treatment is achieved, but lack of specific binding properties and pharmacokinetic profiles reduces therapeutic effectiveness
Solution Approach 1:
The patent applies parameter changes by systematically modifying the binding parameters of the antibodies against LRP5. This includes optimizing affinity, selectivity, and pharmacokinetic properties through controlled variable changes in the antibody structure and characteristics to achieve the desired therapeutic profile.
Solution Approach 2:
The patent segments the antibody structure into specific functional regions with defined binding characteristics. By dividing the antibody into distinct segments with specific binding properties, the invention achieves precise control over which LRP5 epitopes are targeted and how the antibody interacts with the LRP5-Wnt signaling complex.
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 polypeptides effectively inhibit Wnt signaling in cancer cells, inducing tumor regression and reducing side effects, offering improved therapeutic efficacy and safety for treating cancers like TNBC and NSCLC.
Implementation Method 1
The polypeptide binds to low-density lipoprotein receptor-like protein 5 (LRP5)
Implementation Method 2
optional albumin binding moieties for extended half-life
Data Source
AI summary
The invention provides novel LRP5-binding polypeptides, and more specifically novel LRP5-binding immunoglobulin single variable domain constructs which can inhibit Wnt signaling pathways. The invention also relates to specific sequences of such polypeptides, methods of their production, and methods of using them, including methods of treatment of diseases such as cancer.