Humanized Anti-PD-1 Antibodies for Reduced Human Immunogenicity
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Solution Overview
Problem
There is a need for antibodies or antigen-binding portions that can neutralize/block PD-1 negative signals and stimulate an immune response, particularly for the treatment of cancer and other diseases, as existing monoclonal antibodies developed in mice are immunogenic in humans.
Innovation Solution
Development of humanized monoclonal antibodies and antigen-binding fragments that specifically bind to PD-1, with complementarity determining regions (CDRs) showing at least 80% identity to specific sequences, reducing immunogenicity and enhancing efficacy and safety in humans.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If mouse monoclonal antibodies are used to block PD-1, then the ability to neutralize PD-1 negative signals is achieved, but immunogenicity in humans increases
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence of the antibody variable regions to achieve at least 80% identity to human sequences. This gradual alignment with human immunoglobulin sequences reduces the immunogenic difference between the therapeutic antibody and the human immune system, thereby decreasing immunogenicity while preserving the antibody's ability to bind and neutralize PD-1
Solution Approach 2:
The patent uses humanized antibody sequences as an intermediary between mouse monoclonal antibodies and human immune system. By creating chimeric and humanized antibodies with progressively higher human sequence identity (80% or more), the invention bridges the gap between non-human therapeutic antibodies and human biology, reducing rejection while maintaining therapeutic efficacy
2Object-affected harmful factors
If humanized antibodies with high sequence identity are developed, then immunogenicity is reduced, but manufacturing complexity increases
Solution Approach 1:
The patent segments the antibody structure into distinct functional regions: the CDRs which provide antigen binding specificity, and the framework regions which provide structural support and can be humanized. By selectively humanizing framework regions while preserving CDR sequences, the invention reduces immunogenicity without compromising binding function, and enables modular manufacturing approaches
Solution Approach 2:
The patent applies local quality by humanizing specific regions of the antibody (framework regions) while maintaining the original mouse sequences in critical functional areas (CDRs). This localized modification strategy allows the antibody to be partially humanized (80% or more identity) to reduce immunogenicity while preserving the essential antigen-binding properties, balancing manufacturing complexity with therapeutic benefit
Data Source
AI summary
This disclosure relates to isolated monoclonal antibodies or antigen-binding fragments thereof that specifically bind to PD-1 and block the interaction between PD-1 and PD-L1/PD-L2. The disclosure also relates to antibodies that are chimeric, humanized, bispecific, derivatized, single chain antibodies, portions of fusion proteins or bispecific antibodies. Nucleic acid molecules encoding the antibodies, hybridomas, and methods for expressing antibodies are also provided. Pharmaceutical compositions comprising the antibodies are also provided. This disclosure also provides use of these antibodies to enhance T-cell function and upregulate cell-mediated immune responses for the treatment and prevention of various diseases.