Antibodies Targeting Integrin Alpha-V Beta-8 for Selective TGF-Beta Inhibition
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Solution Overview
Problem
Current treatments for disorders associated with elevated TGF-β activity, such as fibrotic lung diseases and cancers, face challenges in selectively inhibiting TGF-β activation without affecting cell adhesion properties, and existing antibodies may have undesirable systemic effects.
Innovation Solution
Development of antibodies like 11E8 and h37E1B5 that specifically bind to αvβ8, inhibiting the release of active TGFβ peptide without interfering with latent TGFβ adhesion, and can distinguish αvβ8 expression levels, allowing for targeted therapy and diagnosis of associated disorders.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If pan-TGF-β neutralizing antibodies are used to inhibit TGF-β activity, then TGF-β signaling is blocked, but systemic side effects occur due to non-selective inhibition of all TGF-β isoforms
Solution Approach 1:
The patent segments the TGF-β inhibition function by developing antibodies that specifically target only TGF-β1 or TGF-β2 isoforms rather than all TGF-β isoforms. This selective inhibition approach divides the broad neutralization function into specific isoform-targeted actions, allowing therapeutic intervention in diseases driven by specific TGF-β isoforms while preserving the functions of other isoforms, thereby reducing systemic side effects
Solution Approach 2:
The patent applies local quality by creating antibodies with specific binding properties tailored to particular TGF-β isoforms. The antibodies are designed with specific epitope recognition capabilities that confer selective affinity for TGF-β1 or TGF-β2, enabling localized and targeted inhibition of pathogenic TGF-β activity in specific disease contexts without affecting other TGF-β isoforms systemically
2Reliability
If existing anti-αvβ8 antibodies are used to inhibit TGF-β activation, then TGF-β release is blocked, but cell adhesion functions are also affected
Solution Approach 1:
The patent applies local quality by developing antibodies with differential binding characteristics that allow selective interference with TGF-β activation while preserving cell adhesion. The antibodies are engineered to bind specific conformational epitopes on αvβ8 that are involved in TGF-β activation but not in cell adhesion, thereby achieving localized functional inhibition without affecting other αvβ8 functions
Solution Approach 2:
The patent employs an inverted approach by designing antibodies that bind to αvβ8 in a manner that prevents TGF-β activation through a mechanism opposite to natural activation. Instead of blocking the natural binding interface, the antibodies bind to alternative epitopes that induce conformational changes or steric hindrance specifically interfering with TGF-β release while leaving cell adhesion capability intact
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
These antibodies effectively reduce TGFβ signaling in individuals with conditions like inflammatory bowel disease and pulmonary fibrosis, offering a targeted therapeutic approach with minimal side effects by selectively inhibiting TGFβ activation while preserving cell adhesion functions.
Implementation Method 1
isolated antibody that specifically binds αvβ8, wherein the isolated antibody inhibits release of active, mature TGFβ peptide
Implementation Method 2
allowing for targeted therapy and diagnosis of associated disorders
Data Source
AI summary
Provided herein are antibodies with high affinity for the β8 subunit of αvβ8.