Humanized Anti-PSMA Antibody With Reduced Immunogenicity
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Solution Overview
Problem
The challenge lies in developing a humanized version of the murine anti-PSMA antibody 5D3 that retains its favorable properties, such as high affinity and specificity for PSMA, while minimizing the immune response typically elicited by murine antibodies in humans.
Innovation Solution
A humanized antibody is developed with specific amino acid sequences for the VH and VL regions, including certain CDRs, that maintain the nanomolar affinity and single target specificity of the parent 5D3 antibody, while replacing mouse framework regions with human sequences to reduce immunogenicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a murine anti-PSMA antibody is used, then high affinity and specificity for PSMA are achieved, but an adverse immune response is elicited in humans
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence parameters of the antibody framework regions. Specifically, mouse framework regions are replaced with human framework regions while preserving the CDR sequences, thereby changing the immunogenicity parameter while maintaining binding affinity. This humanization process transforms the antibody from murine to humanized format, reducing the adverse immune response while retaining PSMA binding capability.
Solution Approach 2:
The patent creates a composite antibody structure combining human framework regions with murine CDR regions. This chimeric construction integrates the low immunogenicity of human sequences with the high specificity of murine CDRs, achieving a hybrid antibody that exhibits both desired binding properties and reduced immune recognition.
2Object-affected harmful factors
If humanized antibody sequences are developed, then immune response is reduced, but maintaining nanomolar affinity becomes challenging
Solution Approach 1:
The patent applies local quality by preserving the CDR regions (complementarity-determining regions) in their original murine sequences while replacing only the framework regions with human sequences. The CDRs are the local regions responsible for antigen binding, so maintaining their original sequence ensures high affinity binding is preserved. Meanwhile, the framework regions are localized to provide structural support and are humanized to reduce immunogenicity.
3Object-affected harmful factors
If mouse framework regions are replaced with human sequences, then immunogenicity is reduced, but production yield may be affected
Solution Approach 1:
The patent optimizes expression parameters by selecting appropriate human framework region sequences and configuring the antibody gene construct for mammalian expression systems. The humanized sequences are designed to be compatible with human cell line expression (such as HEK293 or CHO cells), ensuring proper folding, assembly, and secretion while maintaining high production yields. Expression conditions including temperature, media composition, and cell density are optimized to maximize antibody production.
Data Source
AI summary
The present invention relates to antibodies that bind to prostate-specific membrane antigen (PSMA).