Humanized Anti-TF-Antigen Antibodies Reducing Immunogenicity
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Solution Overview
Problem
Current monoclonal antibodies targeting the Thomsen-Friedenreich (TF) human tumor antigen are limited by immunogenicity and specificity issues, failing to effectively inhibit cancer cell growth and metastasis in human cancers.
Innovation Solution
Development of partially humanized monoclonal antibodies and fragments that specifically bind to TF-Ag, incorporating murine and human immunoglobulin sequences to maintain specificity and reduce immunogenicity, with enhanced antibody-dependent cytotoxicity and internalization capabilities.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If murine monoclonal antibodies are used to target TF-Ag, then binding specificity is achieved, but immunogenicity increases and therapeutic efficacy decreases
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequences of the antibody framework regions while maintaining the complementarity determining regions (CDRs) from the original murine antibody. This creates humanized antibodies with human framework sequences that reduce immunogenicity while preserving the murine CDR sequences that provide specific binding to TF-Ag. The framework regions are systematically replaced with human sequences to change the immunological parameters of the antibody.
Solution Approach 2:
The patent segments the antibody into distinct functional regions: the complementarity determining regions (CDRs) that maintain antigen specificity and the framework regions that are humanized to reduce immunogenicity. This segmentation allows independent optimization of each region's properties - the CDRs are kept murine for specificity while the frameworks are made human for reduced immunogenicity.
2Measurement precision
If conventional monoclonal antibodies are used, then TF-Ag binding is achieved, but tumor growth inhibition is insufficient
Solution Approach 1:
The patent creates composite antibody molecules that combine the best features of murine and human antibodies. The variable regions incorporate murine CDR sequences for high-affinity TF-Ag binding, while the constant and framework regions use human sequences for reduced immunogenicity and improved pharmacokinetics. This composite approach yields antibodies with both strong binding and effective tumor growth inhibition.
Solution Approach 2:
The patent copies the successful binding features of murine antibodies into humanized versions by transferring the CDR sequences while replacing the framework sequences. This copying strategy preserves the functional binding capability while adapting the antibody to the human immune system, thereby maintaining tumor growth inhibition efficacy.
Data Source
AI summary
Provided are humanized monoclonal antibodies (mAbs) or fragments thereof that bind with specificity to the Thomsen-Friedenreich (TF) human tumor antigen. Three distinct variable heavy and three variable light chains are provided, and can be combined to make a total of twenty-five distinct heavy and light chain combinations. Methods of using the mAbs and fragments thereof for cancer therapy and diagnostic imaging are provided, as are methods for making the mAbs and fragments thereof. In vitro cell cultures that express the mAbs and fragments thereof, and kits are also provided.