LTBP-Complex-Specific TGFβ Inhibitors for Fibrosis
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Solution Overview
Problem
Current TGFβ inhibitors face challenges due to toxicities associated with broad inhibition of TGFβ, leading to discontinued clinical programs and adverse effects such as heart valve lesions, physeal dysplasia, multiple organ toxicities, and induction of epithelial hyperplasia and skin rashes.
Innovation Solution
Development of isoform-specific, context-selective TGFβ1 inhibitors that selectively target matrix-associated TGFβ1 activation without inhibiting immune cell-associated TGFβ1 activation, using monoclonal antibodies with high affinities for LTBP1- and/or LTBP3-presented proTGFβ complexes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If broad inhibition of TGFβ is achieved using pan-TGFβ inhibitors, then tumor growth inhibition and anti-angiogenic effects are improved, but toxicities such as heart valve lesions, physeal dysplasia, multiple organ toxicities, and immune system activation occur
Solution Approach 1:
The patent segments the TGFβ inhibition function by targeting specific isoforms (TGFβ1 and TGFβ2) rather than all TGFβ isoforms equally. The inhibitors are designed to selectively inhibit TGFβ1 and TGFβ2 while having reduced or no activity against TGFβ3, thereby dividing the inhibition function across specific targets to reduce off-target toxicities while maintaining anti-tumor efficacy.
Solution Approach 2:
The patent applies local quality by creating inhibitors with differentiated binding affinities for different TGFβ isoforms. The inhibitors exhibit high affinity for TGFβ1 and TGFβ2 (enabling tumor inhibition) but low or no affinity for TGFβ3 (avoiding immune activation and associated toxicities). This localized selectivity allows the inhibitor to provide therapeutic effects only where needed without causing system-wide adverse effects.
2Reliability
If pan-TGFβ inhibitors are used to target all TGFβ isoforms, then comprehensive signaling inhibition is achieved, but immune system activation and autoimmunity risk increase
Solution Approach 1:
The patent extracts the harmful function of immune activation by selectively removing inhibition of TGFβ3 from the therapeutic action. By designing inhibitors that do not effectively bind or inhibit TGFβ3, the patent separates the beneficial tumor-inhibiting function (via TGFβ1/2 inhibition) from the harmful immune-activating function, thereby eliminating autoimmunity risk while maintaining anti-tumor efficacy.
3Ease of operation
If small molecule TGFβ inhibitors are developed, then oral bioavailability and ease of administration are improved, but toxicities such as heart valve lesions and physeal dysplasia occur
Solution Approach 1:
The patent changes the molecular parameters of the inhibitors to achieve isoform-selective binding. By modifying the chemical structure and binding characteristics of the inhibitors, the patent creates molecules that preferentially bind TGFβ1 and TGFβ2 over TGFβ3, thereby changing the pharmacological profile to reduce organ-specific toxicities while maintaining oral bioavailability and ease of administration.
Data Source
AI summary
Disclosed herein are inhibitors, such as antibodies, and antigen-binding portions thereof, that selectively bind complexes of LTBP1-TGFβ and/or LTBP3-TGFβ. The application also provides methods of use of these inhibitors for, for example, inhibiting TGFβ activation, and treating subjects suffering from TGFβ-related disorders, such as fibrotic conditions. Methods of selecting a context-dependent or context-independent isoform-specific TGFβ inhibitor for a subject in need thereof are also provided.