Splicing Modulator ADCs for Selective HER2 and EPHA2 Tumor Targeting

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Solution Overview

Problem

Current cancer treatments targeting HER2, CD138, and EPHA2 antigens face challenges in effectively inhibiting tumor growth and overcoming resistance through splicing modulation, as existing therapies do not adequately exploit the potential of splicing dysregulation in cancer cells.

Innovation Solution

Development of antibody-drug conjugates (ADCs) that combine antibodies or antigen binding fragments targeting HER2, CD138, or EPHA2 with splicing modulators, linked by specific linkers, allowing internalization and splicing modulation within cancer cells to inhibit tumor growth.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If splicing modulators are used to treat cancer, then splicing dysregulation is modulated, but the modulators cannot selectively target cancer cells without affecting normal cells

Engineering Contradiction:

Improveselectivity of splicing modulationVSAvoidspecificity to cancer cells

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent introduces an antibody as an intermediary carrier that specifically binds to cancer cell surface antigens (HER2, CD138, or EPHA2). This antibody-splicing modulator conjugate system allows the splicing modulator to be delivered selectively to cancer cells through the antibody's specific recognition, resolving the contradiction between achieving splicing modulation and ensuring cancer cell specificity.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If conventional cancer therapies are used, then tumor growth is targeted, but resistance develops and treatment efficacy is reduced

Engineering Contradiction:

Improvetreatment efficacyVSAvoidduration of treatment response

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The patent changes the therapeutic parameter from conventional cytotoxic mechanisms to splicing modulation, a fundamentally different mechanism of action. By targeting the splicing machinery (SF3b complex) rather than traditional cell death pathways, the treatment can overcome resistance that has developed against conventional therapies, thereby extending the duration of effective treatment response.

Inventive Principle:

Principle #35Parameter changes

3Reliability

If splicing modulators are administered systemically, then splicing is modulated throughout the body, but off-target effects and toxicity increase

Engineering Contradiction:

Improveprecision of splicing modulationVSAvoidoff-target effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The antibody serves as a targeted delivery vehicle that directs the splicing modulator specifically to cancer cells expressing the target antigen. This localized delivery through the antibody intermediary prevents systemic distribution of the splicing modulator, thereby reducing off-target effects and toxicity while maintaining precise splicing modulation at the disease site.

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS12514926B2Splicing modulator antibody-drug conjugates and methods of use

Publication Date: 2026.01.06 EISAI R&D MANAGEMENT CO LTD

AI summary

Linker-drug compounds and antibody-drug conjugates that bind to human oncology targets are disclosed. The linker-drug compounds and antibody-drug conjugates comprise a splicing modulator drug moiety. The disclosure further relates to methods and compositions for use in the treatment of neoplastic disorders by administering the antibody-drug conjugates provided herein. In an embodiment, the splicing modulator comprises a pladienolide or a pladienolide derivative.