GARP-TGFβ1 Binding Molecules for Selective Tumor Immunosuppression Blockade

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Solution Overview

Problem

Current treatments targeting mature TGFβ1 exhibit dose-dependent toxicity, and there is a need for drugs that can bind to TGFβ1 precursor proteins or complexes with high affinity to treat TGFβ-associated diseases like tumors and fibrosis without causing significant side effects.

Innovation Solution

Development of a TGFβ1-binding molecule, specifically a GARP-TGFβ1-binding molecule, comprising variable regions with defined complementarity-determining regions (CDRs) that selectively inhibit TGFβ1 activity by binding to TGFβ1 precursor proteins or complexes, reducing toxicity and enhancing therapeutic efficacy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If pan-TGFβ antibodies targeting mature TGFβ1 are used, then TGFβ1 activity is inhibited, but dose-dependent in vivo toxicity occurs

Engineering Contradiction:

ImproveTGFβ1 inhibition efficacyVSAvoidin vivo toxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The invention segments the TGFβ1 inhibition approach by specifically targeting the GARP-TGFβ1 complex rather than all TGFβ1 forms. The antibody of the present disclosure binds selectively to the GARP-TGFβ1 complex, excluding other TGFβ1 complexes such as LTBP1-TGFβ1, LTBP3-TGFβ1, and LRRC33-TGFβ1, thereby achieving selective inhibition that reduces off-target toxicity while maintaining therapeutic efficacy

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The invention applies local quality by directing the antibody to a specific location and form of TGFβ1 (the GARP-TGFβ1 complex produced by Tregs and tumor cells in the tumor microenvironment) rather than all TGFβ1 throughout the body. This localized targeting approach allows for effective tumor microenvironment modulation while minimizing systemic toxicity

Inventive Principle:

Principle #3Local quality

2Reliability

If anti-PD-1 antibody is used for tumor immunotherapy, then immune checkpoint inhibition is achieved, but total response rate remains low at about 20%

Engineering Contradiction:

Improveimmune checkpoint inhibitionVSAvoidresponse rate

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The invention merges two therapeutic approaches by combining GARP-TGFβ1 complex inhibition with anti-PD-1 antibody therapy. The antibody of the present disclosure specifically binds to the GARP-TGFβ1 complex, and when combined with anti-PD-1 antibody, this combination therapy addresses both TGFβ1-mediated immunosuppression and PD-1 checkpoint inhibition, thereby overcoming tumor immune evasion more effectively and increasing response rates

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The GARP-TGFβ1 complex inhibition acts as an intermediary mechanism that enhances the effectiveness of anti-PD-1 therapy. By blocking the GARP-TGFβ1 complex, the invention removes a key immunosuppressive pathway that tumors use to evade PD-1 checkpoint inhibition, thereby serving as a mediator that amplifies the therapeutic effect of anti-PD-1 antibodies

Inventive Principle:

Principle #24Intermediary (Mediator)

3Reliability

If TGFβ1 precursor proteins or TGFβ1 complexes are targeted, then TGFβ1 production at source is inhibited, but currently no commercially available antibodies exist with high affinity binding

Engineering Contradiction:

ImproveTGFβ1 production inhibitionVSAvoidbinding affinity

Core Design Contradiction:

ReliabilityVSManufacturing precision

Solution Approach 1:

The invention replaces the need for complex multi-step TGFβ1 activation inhibition with a direct antibody binding mechanism. The antibody of the present disclosure directly binds to the GARP-TGFβ1 complex with high affinity, eliminating the need for multiple sequential interactions and achieving precise inhibition of TGFβ1 production at source through a single, well-defined binding event

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

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 TGFβ1-binding molecule effectively inhibits TGFβ1 activity, reducing immunosuppression and tumor growth, while minimizing adverse reactions and toxicity, offering a safer treatment option for TGFβ-associated diseases.

Implementation Method 1

TGFβ1-binding molecule comprising a heavy chain variable region (VH) and a light chain variable region (VL) that specifically binds to a TGFβ1 precursor protein or a TGFβ1 complex

Methodology Applied

Scientific EffectAntigen-antibody binding:

Implementation Method 2

GARP-TGFβ1-binding molecule comprising at least one immunoglobulin single variable domain that binds to a TGFβ1 complex, preferably a GARP-TGFβ1 complex

Methodology Applied

Scientific EffectSpecific protein-protein binding:

Data Source

PatentEP4650366A1Tgfbeta1 binding molecule, GARP-tgfbeta1 binding molecule and medical use thereof

Publication Date: 2025.11.19 BEIJING TUO JIE BIOPHARMACEUTICAL CO LTD

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AI summary

The present disclosure relates to a TGFβ1 binding molecule, a GARP-TGFβ1 binding molecule and a medical use thereof. In particular, the present disclosure relates to a TGFβ1 binding molecule, a GARP-TGFβ1 binding molecule, a pharmaceutical composition comprising same, a preparation method therefor and a medical use thereof. The present disclosure further relates to a method for treating and/or preventing diseases (e.g., tumors or cancer) by using the TGFβ1 binding molecule, the GARP-TGFβ1 binding molecule, and the pharmaceutical composition comprising same.