4-1BB Agonist Combination Therapy With HER-2 Targeting

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Solution Overview

Problem

Current immune-based therapies for cancer, particularly those targeting HER-2, are only effective in a proportion of patients and often lead to unacceptable toxicity, necessitating the development of safer and more effective combination therapies.

Innovation Solution

A combination therapy using 4-1BB agonists, specifically 4-1BBL trimer containing antigen binding molecules, in conjunction with HER-2 targeting agents such as trastuzumab, pertuzumab, or trastuzumab emtansine, to enhance tumor cell inhibition and elimination.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current immune-based therapies targeting HER-2 are used, then tumor cell inhibition is achieved, but unacceptable toxicity occurs

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidtoxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent divides the therapeutic approach into two distinct components: a HER-2 targeting agent and a 4-1BB agonist. This segmentation allows each component to perform its specific function with optimized safety and efficacy profiles, avoiding the toxicity of single-agent high-dose therapies while maintaining synergistic anti-tumor activity

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The 4-1BB agonist acts as an intermediary that enhances the immune system's ability to recognize and attack HER-2 positive tumor cells. By stimulating 4-1BB receptors on T cells, the agonist amplifies the anti-tumor response initiated by the HER-2 targeting agent, reducing the need for high doses of cytotoxic agents and thereby lowering toxicity

Inventive Principle:

Principle #24Intermediary (Mediator)

2Ease of operation

If HER-2 targeting agents are used alone, then treatment is simpler, but therapeutic benefit is insufficient for many patients

Engineering Contradiction:

Improvetreatment simplicityVSAvoidtherapeutic benefit

Core Design Contradiction:

Ease of operationVSReliability

Solution Approach 1:

The patent merges HER-2 targeted therapy with 4-1BB immune checkpoint activation into a combination regimen. This merging leverages the complementary mechanisms of action: HER-2 targeting provides direct anti-tumor effects and immune modulation, while 4-1BB agonism enhances T cell-mediated immunity, together providing superior therapeutic benefit compared to either agent alone

Inventive Principle:

Principle #5Merging (Combining)

3Reliability

If Fc-mediated crosslinking is used for 4-1BB agonists, then immune activation occurs, but unspecific toxicity increases

Engineering Contradiction:

Improveimmune activationVSAvoidunspecific toxicity

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent employs 4-1BB agonists with modified Fc regions that have reduced or abolished binding to Fcγ receptors. This local modification of the Fc region eliminates unspecific Fc-mediated crosslinking and associated toxicity while preserving the desired 4-1BB receptor activation and immune stimulation effects

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS20250340614A1Combination therapy with targeted 4-1BB (CD137) agonists

Publication Date: 2025.11.06 F HOFFMANN LA ROCHE INC

AI summary

The present invention relates to combination therapies employing 4-1BB (CD137) agonists, in particular 4-1BBL trimer containing antigen binding molecules, in combination with HER-2 targeting agents, the use of these combination therapies for the treatment of cancer, and methods of using the combination therapies.