Multispecific LTBR-EDB Binding Molecules for Tumor-Specific Immune Activation

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Solution Overview

Problem

Current anti-cancer immunotherapies, such as those targeting the lymphotoxin beta receptor (LTBR), face challenges in specificity, leading to systemic immune-related adverse events due to broad expression of LTBR in the organism, and lack therapeutic modalities that can activate LTBR specifically in tumors without activating normal tissues.

Innovation Solution

Development of multispecific binding molecules, like bispecific antibodies, that specifically bind to LTBR and extra-domain B (EDB) of fibronectin, activating LTBR only in the presence of EDB, thereby reducing the risk of unwanted immune activation in normal tissues.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If LTBR is targeted with immunotherapy to activate anti-tumor immune responses, then anti-tumor efficacy is improved, but systemic immune-related adverse events occur due to broad LTBR expression in normal tissues

Engineering Contradiction:

Improveanti-tumor efficacyVSAvoidsystemic immune-related adverse events

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The binding molecule is divided into two distinct binding domains: a first binding domain that specifically binds to LTBR and a second binding domain that specifically binds to EDB. This segmentation allows the molecule to require simultaneous binding to both targets for activation, thereby achieving tissue-specific activation only in tumors expressing both LTBR and EDB, while avoiding activation in normal tissues expressing only LTBR.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

EDB serves as an intermediary target that is selectively expressed in the tumor microenvironment. By requiring binding to both LTBR and EDB, the molecule uses EDB as a mediator to ensure activation occurs only in the tumor context, not in normal tissues where LTBR is expressed but EDB is absent.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Productivity

If LTBR is activated to promote immune cell infiltration and TLS formation, then anti-tumor immune response is enhanced, but unwanted immune activation in normal tissues occurs

Engineering Contradiction:

Improveimmune cell infiltrationVSAvoidunwanted immune activation

Core Design Contradiction:

ProductivityVSObject-generated harmful factors

Solution Approach 1:

The binding molecule exhibits local quality by being activated only in the specific microenvironment where both LTBR and EDB are co-expressed (tumor tissues). The molecule remains inactive in normal tissues lacking EDB, thereby achieving localized immune stimulation only where needed for anti-tumor response.

Inventive Principle:

Principle #3Local quality

3Reliability

If multispecific binding molecules are designed to bind both LTBR and EDB, then tumor-specific activation is achieved, but molecule complexity increases

Engineering Contradiction:

Improvetumor-specific activationVSAvoidmolecule structure

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent merges two separate binding specificities (LTBR binding and EDB binding) into a single multispecific binding molecule. This combining approach achieves tumor-specific activation through dual binding requirements while using a unified molecular structure that can be produced as a single therapeutic entity, avoiding the need for combination therapies.

Inventive Principle:

Principle #5Merging (Combining)

Data Source

PatentUS20250101123A1Multispecific binding molecules comprising LTBR and EDB binding domains and uses thereof

Publication Date: 2025.03.27 CILAG GMBH INTERNATIONAL

AI summary

Provided herein are anti-LTBR multispecific binding molecules, nucleic acids encoding the anti-LTBR multispecific binding molecules, vectors comprising the nucleic acids, host cells comprising the vectors, and pharmaceutical compositions comprising the anti-LTBR multispecific binding molecules. Also provided are methods of treating cancer in a subject in need thereof, the methods comprising administering the pharmaceutical compositions disclosed herein.