PDL-1 Antibody CDR Optimization for Tumor Immune Activation
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Solution Overview
Problem
Current anti-PDL-1 antibodies have limitations in binding affinity and blocking efficiency, necessitating the development of new antibodies that can effectively activate T lymphocytes to combat tumors such as lung cancer, melanoma, renal tumors, ovarian cancer, leukemia, and anemia.
Innovation Solution
The development of monoclonal antibodies, including 5C10, 5C10H1L1, 5C10H1L2, 5C10H2L1, 5C10H2L2, 5F10, and 9F6, which specifically bind to PDL-1, block its interaction with PD-1, and activate T cells by inducing the secretion of IFN-γ and IL-2, utilizing recombinant PDL-1 expressed by mammalian cells and hybridoma technology.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing anti-PDL-1 antibodies are used, then some immune activation effect is achieved, but binding affinity and blocking efficiency are insufficient
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequences of the antibody variable regions (specifically CDR regions) to optimize binding affinity. The patent describes generating multiple antibody variants with different amino acid substitutions at specific positions to improve both binding affinity and blocking efficiency while maintaining the basic antibody structure
Solution Approach 2:
The patent employs composite materials by creating chimeric and humanized antibodies that combine different species' antibody sequences. The patent describes constructing antibodies with human constant regions and modified variable regions from non-human sources, combining the advantages of high affinity binding with reduced immunogenicity
2Reliability
If PDL-1 binds to PD-1, then immune suppression is maintained, but tumor cell attack is inhibited
Solution Approach 1:
The patent applies preliminary anti-action by designing antibodies that pre-block the PDL-1/PD-1 binding interface before the natural interaction can occur. The patent describes generating antibodies that bind to PDL-1 with high affinity and sterically hinder the PD-1 binding site, preventing the formation of the immunosuppressive complex
Solution Approach 2:
The patent uses intermediary molecules (the engineered monoclonal antibodies) to mediate between PDL-1 and PD-1. These antibodies bind to PDL-1 and act as intermediaries that prevent direct PDL-1/PD-1 interaction while simultaneously providing a platform for immune activation through Fc receptor engagement
3Productivity
If T cell activation is enhanced, then tumor cell killing is improved, but immune system complexity increases
Solution Approach 1:
The patent applies universality by designing antibodies with dual functionality: they simultaneously block PDL-1/PD-1 interaction and activate T cells through Fc receptor engagement. The patent describes engineering antibodies with optimized Fc regions that enhance ADCC and CDC activities while maintaining PD-1 pathway blockade, providing multiple mechanisms of action in a single molecule
Data Source
AI summary
The present invention belongs to the field of tumor therapy and molecular immunology, and relates to a PDL-1 antibody, a pharmaceutical composition thereof and use thereof. In particular, the present invention relates to a PDL-1 monoclonal antibody or an antigen-binding fragment thereof, wherein the monoclonal antibody has a heavy chain variable region comprising CDRs as set forth in SEQ ID NOs: 15-17; and/or has a light chain variable region comprising CDRs as set forth in SEQ ID NOs: 18-20. The monoclonal antibody of the present invention can bind to PDL-1 specifically, and specifically remove immunosuppressive function of PDL-1 and activate T lymphocytes.