Anti-PD-1 Antibody CDR Engineering for Selective Binding
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Solution Overview
Problem
Current therapeutic methods for immune disorders such as autoimmune diseases, inflammatory disorders, allergies, transplant rejection, cancer, and immune deficiency lack effective and safe modulation of the immune response, particularly in relation to the PD-1 pathway.
Innovation Solution
Development of anti-PD-1 antibodies or antigen binding fragments with specific VH and VL region amino acid sequences, which can be humanized and used in various forms like Fab, scFv, or linked to other molecules, to bind to PD-1, offering diagnostic and therapeutic applications for cancers and infectious diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If monoclonal antibodies to PD-1 are used for immunotherapy, then therapeutic effectiveness against cancer and infectious diseases is improved, but risk of autoimmune side effects increases
Solution Approach 1:
The patent applies local quality by engineering specific amino acid substitutions in the antibody's complementarity-determining regions (CDRs) to create variants with differentiated binding characteristics. These localized sequence modifications allow the antibody to maintain PD-1 binding while reducing affinity for PD-L1, thereby achieving selective inhibition that preserves therapeutic effectiveness while minimizing autoimmune side effects.
Solution Approach 2:
The patent employs parameter changes by systematically varying amino acid sequences in the antibody variable regions (specifically in H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2, and L-CDR3) to modulate binding affinity parameters. This allows optimization of the therapeutic window by adjusting the balance between PD-1 binding strength and PD-L1 cross-reactivity, thereby improving safety while maintaining efficacy.
2Object-affected harmful factors
If antibody sequences are humanized to reduce immunogenicity, then safety profile is improved, but binding affinity to PD-1 may be reduced
Solution Approach 1:
The patent applies local quality by selectively humanizing only certain framework regions while preserving the critical CDR regions that determine PD-1 binding affinity. This localized approach allows the antibody to maintain high binding affinity through conserved CDR sequences while reducing immunogenicity through humanized framework regions that match human germline sequences.
Solution Approach 2:
The patent employs composite materials by creating chimeric antibody structures that combine human and non-human (e.g., murine or rabbit) sequence elements. The composite architecture integrates human framework regions for reduced immunogenicity with non-human CDR regions or specific amino acid substitutions that maintain or enhance PD-1 binding affinity, achieving both safety and efficacy.
3Object-affected harmful factors
If antibody variants with modified amino acid sequences are developed to reduce PD-L1 binding, then autoimmune side effects are reduced, but therapeutic coverage may be limited
Solution Approach 1:
The patent applies universality by designing antibody variants that maintain broad therapeutic coverage through conserved binding to the PD-1 receptor across different tissue types and disease contexts. The amino acid substitutions are strategically placed to reduce PD-L1 binding specifically while preserving PD-1 engagement, ensuring the antibody remains effective across multiple therapeutic indications including cancer, chronic infections, and autoimmune diseases without limiting adaptability.
Data Source
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AI summary
Provided are monoclonal antibody, particularly rabbit recombinant antibody, which specifically binds to human PD-1 with biological functions and super high affinity, and methods of use. In various embodiments, the antibodies are fully humanized antibodies that bind to human PD-1. Nucleic acid molecules encoding the antibodies and methods for expressing the antibodies are also provided. In some embodiments, the antibodies are useful for inhibiting or neutralizing PD-1 activity, thus providing a means of treating, preventing and/or diagnosing a disease or disorder such as cancer or a viral infection.