Anti-CD27 Antibodies with Enhanced Binding Affinity
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Solution Overview
Problem
Current anti-CD27 antibodies lack improved characteristics for binding to human CD27, particularly with the A59T SNP, and do not effectively cross-react with cynomolgus monkeys, limiting their therapeutic efficacy in immune stimulation for cancer and infectious diseases.
Innovation Solution
Development of anti-CD27 antibodies and antigen binding fragments with specific heavy and light chain variable region sequences that provide enhanced binding affinity, cross-reactivity with human and cynomolgus CD27, and the ability to induce NF-κB activation and increase T cell activation, including those with amino acid sequences specified in SEQ ID NOs, to stimulate immune responses effectively.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing anti-CD27 antibodies are used, then basic binding to human CD27 is achieved, but binding affinity to human CD27 with A59T SNP and cross-reactivity with cynomolgus monkey CD27 are insufficient
Solution Approach 1:
The patent applies parameter changes by modifying the antibody variable region sequences to achieve optimal binding characteristics. Specifically, the heavy chain variable region sequences (SEQ ID NOs: 9-13, 32-39) and light chain variable region sequences (SEQ ID NOs: 14-18, 33-40) are engineered to provide high affinity binding to human CD27 including the A59T SNP variant, while maintaining cross-reactivity with cynomolgus monkey CD27. This sequence optimization represents a parameter change in the antibody structure to simultaneously improve binding affinity and adaptability.
Solution Approach 2:
The patent achieves universality by designing antibodies that can bind to multiple CD27 variants across different species. The anti-CD27 antibodies described in the patent bind to human CD27 (including A59T SNP), human CD27 from different sources, and cynomolgus monkey CD27 with high affinity. This multi-functional binding capability allows the same antibody to be effective across different biological systems and species, resolving the contradiction between specific binding affinity and cross-reactivity.
2Reliability
If anti-CD27 antibodies are designed for high binding affinity to human CD27, then therapeutic efficacy in human cancer treatment is improved, but cross-reactivity with cynomolgus monkey CD27 may be compromised
Solution Approach 1:
The patent employs parameter changes through careful selection and optimization of variable region sequences. The heavy chain variable regions (SEQ ID NOs: 9-13, 32-39) and light chain variable regions (SEQ ID NOs: 14-18, 33-40) are specifically engineered to recognize conserved epitopes on CD27 that are present in both human and cynomolgus monkey, while maintaining high affinity for human CD27 including the A59T SNP variant. This sequence engineering approach allows the antibody to distinguish between species-specific differences while maintaining broad reactivity.
Solution Approach 2:
The patent applies local quality by focusing the antibody binding interface on specific conserved regions of the CD27 molecule. The variable regions are designed to target epitopes that are locally conserved across human and cynomolgus monkey CD27, particularly in areas that are critical for both high affinity binding and cross-species recognition. This localized focus on conserved epitopes allows the antibody to achieve high specificity for human CD27 while maintaining cross-reactivity with cynomolgus monkey CD27.
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 antibodies demonstrate improved binding properties, inducing significant NF-κB activation and T cell activation, enhancing immune responses and therapeutic potential for cancer and infectious disease treatment.
Implementation Method 1
anti-CD27 antibodies and antigen binding fragments comprising the structural and functional features specified below... binds to human CD27 with an EC50 of less than 100 pM
Implementation Method 2
induces NF-κB activation in human CD27 expressing cells with an EC50 of less than 5 nM when the antibody or fragment thereof is in soluble form
Implementation Method 3
increases T cell activation; stimulates antigen-specific T-cell production of IL-2 and IFNγ
Data Source
AI summary
The present invention relates to anti-CD27 antibodies, as well as use of these antibodies in the treatment of diseases such as cancer and infectious disease.