Humanized GPC3 Antibody High Affinity Binding

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Solution Overview

Problem

Current GPC3-targeting antibodies, such as codrituzumab, have shown limited effectiveness in clinical trials for hepatocellular carcinoma, necessitating the development of more potent and specific humanized antibodies that can effectively bind to GPC3-positive tumor cells.

Innovation Solution

A humanized antibody or antigen-binding fragment specifically designed to bind to GPC3, comprising humanized heavy and light chain variable regions with defined complementarity determining regions (CDRs) and framework regions, optimized for high affinity and specificity to GPC3, potentially combined with effector molecules or chimeric antigen receptors for enhanced therapeutic efficacy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If codrituzumab (GC33 antibody) is used to target GPC3 in hepatocellular carcinoma, then antibody-dependent cellular cytotoxicity is produced, but clinical effectiveness is limited and patient outcomes are not significantly improved

Engineering Contradiction:
Improveclinical effectivenessVSAvoidanti-tumor effect
Core Design Contradiction:
ReliabilityVSProductivity

Solution Approach 1:

The patent applies parameter changes by modifying the antibody's binding characteristics through humanization processes. The antibody sequence is optimized to achieve higher affinity binding to GPC3, with specific focus on improving the complementarity determining regions (CDRs) while maintaining human framework regions. This results in an antibody with enhanced binding parameters that can more effectively engage GPC3-positive tumor cells, thereby improving clinical effectiveness and anti-tumor effects compared to the original codrituzumab.

Inventive Principle:
Principle #35Parameter changes

2Productivity

If high dose of codrituzumab is administered to improve patient outcomes, then anti-tumor effects may be enhanced, but immune tolerance and safety profile become more concerning

Engineering Contradiction:
Improveanti-tumor effectVSAvoidimmune tolerance
Core Design Contradiction:
ProductivityVSObject-affected harmful factors

Solution Approach 1:

The patent achieves improved anti-tumor effects without requiring high doses by changing the binding affinity parameter of the antibody. The humanized antibody design with optimized CDRs and framework regions creates a more potent antibody that can achieve therapeutic efficacy at lower doses, thereby avoiding the immune tolerance and safety issues associated with high-dose administration of the original codrituzumab.

Inventive Principle:
Principle #35Parameter changes

3Reliability

If selection of patients with higher GPC3 expression is performed to improve treatment response, then therapeutic efficacy increases, but patient selection complexity and treatment accessibility decrease

Engineering Contradiction:
Improvetreatment responseVSAvoidpatient selection process
Core Design Contradiction:
ReliabilityVSDevice complexity

Solution Approach 1:

The patent applies universality by designing an antibody with broad binding capability that can effectively engage GPC3 across different tumor types and expression levels. The humanized antibody structure enables it to bind to GPC3-positive cells in a wide range of cancers, making the treatment applicable to a broader patient population without requiring complex selection criteria based on GPC3 expression levels, thereby simplifying the treatment process while maintaining high treatment response rates.

Inventive Principle:
Principle #6Universality (Multi-functionality)

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The humanized antibody achieves specific binding to GPC3 with high affinity, potentially leading to improved anti-tumor effects by enhancing antibody-dependent cellular cytotoxicity and targeted therapy for GPC3-mediated tumors, including hepatocellular carcinoma.

Implementation Method 1

The present invention provides an antibody or an antigen-binding fragment specifically binding to GPC3

Methodology Applied
Scientific EffectAntibody binding:

Implementation Method 2

The GC33 antibody targets GPC3-positive HCC cells and can produce antibody-dependent cellular cytotoxicity (ADCC)

Methodology Applied
Scientific EffectAntibody-dependent cellular cytotoxicity:

Data Source

PatentUS20240301085A1Humanized GPC3 antibody and application thereof
Publication Date: 2024.09.12 SIMCERE ZAIMING PHARMACEUTICAL CO LTD
  • US20240301085A1 patent drawing
  • US20240301085A1 patent drawing
  • US20240301085A1 patent drawing

AI summary

Provided is a humanized antibody or antigen-binding fragment that specifically binds to GPC3. The antibody or antigen-binding fragment has high affinity with GPC3 protein, and can be used in the preparation of drugs for treating tumors and the like. Also provided are a nucleic acid molecule encoding the humanized GPC3 antibody or antigen-binding fragment, an expression vector, a host cell, and a method for preparing the antibody or antigen-binding fragment. Also provided are an immunoconjugate comprising same, a chimeric antigen receptor, an immunocompetent cell, a multispecific molecule, and a pharmaceutical composition. Also provided are a method for detecting GPC3, and a method for treating various GPC3-related disorders including hepatocellular carcinoma.