LRP6 Constructs with Half-Life Extenders for Wnt Inhibition

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Solution Overview

Problem

Current antibody formats for targeting LRP6 are limited by short serum half-life due to renal clearance and endocytosis, and they face challenges in penetrating tumor tissues effectively, especially in immunosuppressive tumor microenvironments, which hampers their therapeutic efficacy in inhibiting the Wnt signaling pathway for cancer treatment.

Innovation Solution

Development of LRP6 constructs comprising at least one LRP6 binding moiety and a half-life extender molecule, such as PEG or HSA, which are designed to inhibit the Wnt signaling pathway without potentiation and exhibit an extended half-life, allowing for prolonged therapeutic benefit.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If LRP6 binding constructs are used to inhibit Wnt signaling, then therapeutic efficacy is improved, but serum half-life is shortened due to renal clearance and endocytosis

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidserum half-life

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The patent modifies the molecular weight parameter of the LRP6 binding construct by conjugating it with half-life extenders (increasing size), which changes its clearance kinetics and extends serum half-life while maintaining therapeutic efficacy

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates a composite construct by combining the LRP6 binding moiety with half-life extender molecules, resulting in a hybrid molecule that exhibits both the target-binding capability of the original construct and the prolonged circulation properties of the extender

Inventive Principle:

Principle #40Composite materials

2Reliability

If LRP6 binding constructs are used to inhibit Wnt signaling, then therapeutic efficacy is improved, but tissue penetration is reduced due to large size

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidmolecular size

Core Design Contradiction:

ReliabilityVSLength of moving object

Solution Approach 1:

The patent optimizes the molecular size parameter by selecting half-life extenders and conjugation strategies that achieve sufficient half-life extension without excessive size increase, balancing tissue penetration capability with circulation duration

Inventive Principle:

Principle #35Parameter changes

3Reliability

If LRP6 binding constructs are used in immunosuppressive tumor microenvironment, then therapeutic efficacy is reduced, but Fc mediated effector function is suppressed

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidimmunosuppression

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent extracts or avoids reliance on Fc-mediated effector functions by designing constructs that primarily work through LRP6 binding and Wnt pathway inhibition, making the therapeutic mechanism independent of immune system functionality in the tumor microenvironment

Inventive Principle:

Principle #2Taking out (Extraction)

Data Source

PatentUSRE47860E1Methods of treating cancer with low density lipoprotein-related protein 6 (LRP6)—half life extender constructs

Publication Date: 2020.02.18 NOVARTIS AG

AI summary

The present invention relates to LRP6 constructs that bind to LRP6 receptor. The LRP6 constructs comprise at least one LRP6 binding moiety and a half-life extender molecule such that the LRP6 construct inhibit the Wnt signaling pathway without potentiation of the Wnt signal. The LRP6 constructs also have an increased half-life to provide more time for the therapeutic benefit.