GRP94 Antibody-Drug Conjugate for Cetuximab-Resistant CRC

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Solution Overview

Problem

Current chemotherapeutic agents for colorectal cancer, such as cetuximab, are not sufficiently effective for a significant portion of patients, leading to resistance and severe side effects, necessitating the development of new therapeutic targets and strategies.

Innovation Solution

An antibody specifically binding to GRP94, engineered with a selenocysteine residue at the C-terminus of each heavy chain, is conjugated with a stable linker to a drug, forming an antibody-drug conjugate (ADC) for targeted cancer treatment.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If chemotherapeutic agents such as cetuximab are used for CRC treatment, then therapeutic effect is improved, but resistance occurs and side effects increase

Engineering Contradiction:

Improvetherapeutic effectVSAvoidside effects and resistance

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The invention segments the therapeutic approach by using an antibody-drug conjugate that separates the targeting function (anti-GRP94 antibody) from the cytotoxic function (drug payload). This allows selective delivery of the drug to GRP94-expressing cancer cells, improving therapeutic effect while reducing systemic side effects compared to conventional chemotherapeutic agents like cetuximab

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The anti-GRP94 antibody serves as an intermediary that selectively binds to GRP94 on cancer cell surfaces, mediating the delivery of the cytotoxic drug specifically to target cells. This intermediary approach enables precise targeting, overcoming resistance mechanisms that affect conventional therapies and reducing harm to non-target tissues

Inventive Principle:

Principle #24Intermediary (Mediator)

2Adaptability or versatility

If conventional chemotherapeutic agents are used, then treatment coverage is broad, but efficacy is insufficient for resistant patients

Engineering Contradiction:

Improvetreatment coverageVSAvoidefficacy

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The invention applies local quality by targeting a specific molecular marker (GRP94) that is overexpressed in many cancers including colorectal cancer. The anti-GRP94 ADC provides localized therapeutic action at the site of GRP94 expression, achieving high efficacy in resistant patients while the broad applicability to GRP94-positive tumors maintains treatment coverage across multiple cancer types

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS20260097129A1Antibody-drug conjugate comprising drug and antibody specifically binding to GRP94 or antigen-binding fragment thereof

Publication Date: 2026.04.09 KOOKMIN UNIV IND ACAD COOP FOUND

AI summary

The present invention relates to: an antibody-drug conjugate comprising a drug and an antibody specifically binding to GRP94 or an antigen-binding fragment thereof; and a pharmaceutical composition for treating cancer, comprising same as an active ingredient. The antibody-drug conjugate of the present invention comprises an antibody specifically targeting GRP94 and having strong internalization activity, and, as a result of conjugation with a cytotoxic agent, effectively inhibits the growth of cetuximab-resistant CRC cell lines including HT29, HCT116, HCT8 and LoVo cells, and thus can be effectively used as a therapeutic agent for various carcinomas in which GRP94 is overexpressed.