HER3 Antibodies Targeting Conformational Epitopes
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Solution Overview
Problem
Current therapies fail to effectively inhibit both ligand-dependent and ligand-independent signaling pathways of the HER3 receptor, particularly in cancers where HER3 is overexpressed, leading to uncontrolled cell growth and progression.
Innovation Solution
Development of antigen binding proteins, such as antibodies or fragments, that bind to a conformational epitope comprising amino acid residues within domain 2 and domain 4 of the HER3 receptor, stabilizing it in an inactive state and preventing activation, allowing concurrent ligand binding without inducing signal transduction.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antibodies bind to HER3, then ligand binding is blocked, but signal transduction inhibition is incomplete
Solution Approach 1:
The antibody binds to a conformational epitope that is segmented across two distinct domains (domain 2 and domain 4) of the HER3 receptor. This segmentation allows the antibody to engage multiple structural elements simultaneously, achieving complete signal transduction inhibition rather than partial inhibition, thereby resolving the contradiction between reliability and complexity.
Solution Approach 2:
The invention merges the binding interactions across domain 2 and domain 4 into a single conformational epitope recognition event. By combining these domain interactions, the antibody achieves synergistic inhibition of both ligand-dependent and ligand-independent signaling pathways, improving reliability without requiring multiple separate binding events.
2Reliability
If antibodies block ligand binding to HER3, then signal transduction is inhibited, but HER3 activation remains partially functional
Solution Approach 1:
The antibody performs preliminary anti-action by stabilizing the HER3 receptor in an inactive conformation before ligand binding can occur. This pre-prevents the conformational changes required for activation, thereby completely blocking both ligand-dependent and ligand-independent signaling pathways and eliminating residual signaling activity.
Solution Approach 2:
The antibody acts as an intermediary that interferes with the ligand-receptor interaction mechanism. By binding to the conformational epitope, the antibody mediates a structural constraint that prevents the receptor from transitioning to an active state, thereby completely inhibiting HER3 activation without leaving residual functionality.
3Reliability
If the antibody binds to conformational epitope comprising domains 2 and 4, then signal transduction is completely blocked, but epitope recognition complexity increases
Solution Approach 1:
The invention transitions from linear/sequential epitope recognition to three-dimensional conformational epitope recognition. By targeting a conformational epitope that spans domains 2 and 4 in spatial proximity, the antibody achieves complete signal transduction blocking through a single binding event, effectively managing the complexity through spatial organization rather than sequential interactions.
Data Source
AI summary
The present invention relates to antibodies or fragments thereof that target a conformational epitope of a HER receptor. In particular, the invention relates to antibodies or fragments thereof that target a conformational epitope of HER3 receptor and compositions and methods of use thereof.