Humanized Anti-PSCA Antibody Reducing Immunogenicity
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Solution Overview
Problem
Current antibody-based therapies for prostate cancer face challenges due to the human immune response against xenogeneic antibodies, leading to rapid clearance and reduced therapeutic efficacy, necessitating the development of humanized antibodies with minimized immunogenicity.
Innovation Solution
Development of humanized antibodies combining a human or humanized immunoglobulin framework with a binding site recognizing the epitope of murine monoclonal antibody 1G8, specifically designed to target prostate stem cell antigen (PSCA), which are engineered to minimize the human anti-mouse antibody response and maintain high affinity and specificity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If murine monoclonal antibodies are used for tumor targeting, then effective tumor targeting is achieved, but rapid clearance occurs due to human anti-murine antibody response
Solution Approach 1:
The patent applies parameter changes by modifying the antibody's species origin parameter from murine to humanized. The humanized antibody retains the tumor-targeting capability of the original murine antibody while changing its immunogenicity parameter, thereby reducing HAMA response and extending antibody persistence in the human body.
Solution Approach 2:
The patent uses a humanized antibody as an intermediary between the murine antibody and the human immune system. The humanized antibody maintains the tumor-targeting function of the murine antibody while being more compatible with the human immune system, thus mediating between effective targeting and reduced immunogenicity.
2Object-affected harmful factors
If humanized antibodies are developed to minimize HAMA response, then immunogenicity is reduced, but binding affinity may decrease
Solution Approach 1:
The patent applies local quality by selectively replacing only the framework regions of the murine antibody with human sequences, while preserving the complementarity-determining regions (CDRs) that are responsible for antigen binding. This localized modification reduces immunogenicity in the framework regions while maintaining high binding affinity through preservation of the CDRs.
Data Source
AI summary
Prostate stem cell antigen (PSCA) is expressed in the majority of prostate cancer patients, making it an ideal target for cancer immunotherapy. Murine monoclonal antibody 1G8 binds to PSCA with nanomolar affinity, but its efficacy as a therapeutic agent is limited by the generation of a HAMA response. The present invention discloses humanized 1G8 antibodies in which the majority of the mouse-derived epitopes have been removed. These humanized antibodies bind PSCA with high affinity and specificity, and have been shown to reduce human bladder tumor take in a nude mouse model. These characteristics make the humanized antibodies of the present invention attractive agents for the treatment and detection of tumors expressing PSCA.