DLL4 Binding Proteins Neutralize Tumor Angiogenesis
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Solution Overview
Problem
There is a need for therapeutic agents that can effectively target the DLL4-Notch pathway to inhibit or prevent tumor angiogenesis and growth, as existing methods like small molecule inhibitors are toxic and affect normal tissue expression.
Innovation Solution
Development of DLL4 binding proteins, including antibodies and antibody fragments, that bind DLL4 with high affinity and neutralize its activity, eliminating the need for humanized proteins and their associated complications.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If small molecule inhibitors of the Notch receptor are used, then Notch receptor function is inhibited, but toxicity increases and normal tissue expression is suppressed
Solution Approach 1:
The patent applies local quality by targeting a specific ligand (DLL4) rather than the receptor itself, creating localized inhibition at the ligand-receptor interaction interface. This allows Notch signaling to be blocked in tumor vessels while preserving normal Notch expression and function in healthy tissues, thereby reducing toxicity and maintaining normal tissue expression.
Solution Approach 2:
The patent uses an intermediary approach by blocking the DLL4 ligand rather than directly inhibiting the Notch receptor. This intermediary strategy prevents the harmful interaction between DLL4 and Notch receptors in tumors while leaving normal Notch signaling intact, thus avoiding the toxicity associated with direct receptor inhibition.
2Reliability
If DLL4 blockade is used, then tumor growth is inhibited, but vascular development defects may occur
Solution Approach 1:
The patent achieves local quality by selectively targeting DLL4 expression in tumor vessels through the use of antibodies that recognize tumor-specific DLL4 variants or conformations. This localized blocking prevents tumor growth while sparing normal vascular development, as normal vessels express different DLL4 forms that are not recognized by the therapeutic antibodies.
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 DLL4 binding proteins effectively inhibit tumor angiogenesis, even in tumors resistant to anti-VEGF therapy, by targeting DLL4, thereby providing a potential treatment for cancer and other angiogenesis-dependent diseases.
Implementation Method 1
proteins that bind DLL4, including antibodies, CDR-grafted antibodies, and binding fragments thereof, that are capable of binding DLL4. Preferably, a binding protein described herein binds DLL4 with high affinity
Data Source
AI summary
Improved DLL4 binding proteins are described, including antibodies, CDR-grafted antibodies, human antibodies, and DLL4 binding fragments thereof, proteins that bind DLL4 with high affinity, and DLL4 binding proteins that neutralize DLL4 activity. The DLL4 binding proteins are useful for treating or preventing cancers and tumors and especially for treating or preventing tumor angiogenesis, and/or other angiogenesis-dependent diseases such as ocular neovascularization, or angiogenesis-independent diseases characterized by aberrant DLL4 expression or activity such as autoimmune disorders including multiple sclerosis.