FAP-Targeted CD40 Bispecific Agonists for Tumor Microenvironment Activation

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Solution Overview

Problem

Current immune-based therapies for cancer, particularly those targeting CD40, face limitations due to dose-limiting side effects and toxicity, with bispecific antigen binding molecules capable of binding to CD40 and Fibroblast Activation Protein (FAP) showing promise but needing optimization for enhanced efficacy and reduced toxicity.

Innovation Solution

Development of bispecific agonistic CD40-antigen binding molecules specifically designed to target FAP, combined with local hypofractionated radiotherapy, to selectively activate antigen-presenting cells within the tumor microenvironment, thereby enhancing anti-tumor immunity while minimizing systemic toxicity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If CD40 agonist therapy is used to activate antigen-presenting cells and enhance anti-tumor immunity, then therapeutic efficacy is improved, but dose-limiting side effects and toxicity increase

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidtoxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by designing a bispecific antigen binding molecule that selectively targets CD40 in the tumor microenvironment through dual binding to FAP (fibroblast activation protein) and CD40. This localization strategy activates antigen-presenting cells specifically at the tumor site while minimizing systemic activation and associated toxicity, thereby resolving the contradiction between therapeutic efficacy and toxicity.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent uses FAP as an intermediary target to achieve indirect CD40 activation in the tumor microenvironment. The bispecific molecule first binds to FAP on tumor-associated fibroblasts, which then facilitates subsequent CD40 engagement on antigen-presenting cells. This intermediary mechanism provides spatial control over CD40 activation, improving efficacy while reducing off-target toxicity.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If systemic CD40 activation is used to enhance immune response, then anti-tumor immunity is improved, but off-target effects and dose-limiting toxicity increase

Engineering Contradiction:

Improveanti-tumor immunityVSAvoidoff-target effects

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The bispecific antigen binding molecule achieves local quality by requiring simultaneous binding to both FAP and CD40 for activation. Since FAP is predominantly expressed in the tumor microenvironment, this dual-targeting mechanism ensures that CD40 activation occurs locally at the tumor site rather than systemically, thereby improving anti-tumor immunity while minimizing off-target effects.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent segments the CD40 activation process into two distinct binding events: first binding to FAP as an anchoring step, then engaging CD40 for immune activation. This segmentation ensures that CD40 is only activated in the presence of FAP, providing spatial specificity and reducing off-target effects throughout the body.

Inventive Principle:

Principle #1Segmentation

Data Source

PatentUS20230340154A1Combination therapy with FAP-targeted CD40 agonists

Publication Date: 2023.10.26 F HOFFMANN LA ROCHE INC

AI summary

The present invention relates to combination therapies employing FAP-targeted CD40 agonists, in particular bispecific antigen binding molecules comprising at least one antigen binding domain capable of specific binding to Fibroblast Activation Protein (FAP) and at least one antigen binding domain capable of specific binding to CD40, and radiotherapy.