TIGIT-Targeting Antibody CDR Optimization for Immune Checkpoint Blockade
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Solution Overview
Problem
Current therapies for cancer treatment lack effective antibodies targeting TIGIT, a key immunosuppressive receptor involved in tumor immunity, which limits the enhancement of anti-tumor immune responses.
Innovation Solution
Development of fully human antibodies and antigen-binding fragments specifically binding to TIGIT, with high affinity and the ability to block TIGIT's interaction with its ligands CD155/CD112, thereby inhibiting inhibitory signals and reducing tumor growth, including the use of ADI-55796 and ADI-55812 antibodies with optimized CDR sequences for enhanced binding and blocking activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If TIGIT blocking monoclonal antibodies are used for therapeutic intervention, then anti-tumor immune response is enhanced, but the availability of effective TIGIT-targeting antibodies was previously limited
Solution Approach 1:
The patent applies parameter changes by optimizing the CDR (complementarity-determining region) sequences of the antibody variable regions to achieve high binding affinity to TIGIT. The specific CDR sequences (VH CDR1: GGSISSYDHY, VH CDR2: VYYSGST, VH CDR3: ARVGPDVSHPPFDY, VL CDR1: QSISSY, VL CDR2: AAS, VL CDR3: QQSYSTPIT) are engineered to maximize binding effectiveness, thereby enhancing the reliability of anti-tumor immune response while providing versatile TIGIT-targeting antibody options.
2Reliability
If antibody affinity to TIGIT is increased to effectively block ligand binding, then immunosuppressive signals are reduced, but developing such high-affinity antibodies presents a technical challenge
Solution Approach 1:
The patent resolves this contradiction by systematically optimizing the CDR region parameters of the antibody. The engineered CDR sequences are designed to achieve high binding affinity to TIGIT, enabling effective blocking of CD155 and CD112 ligand interactions. This parameter optimization approach provides a clear development pathway that reduces the complexity of creating high-affinity TIGIT-blocking antibodies.
3Reliability
If fully human antibodies are developed for TIGIT targeting, then therapeutic effectiveness is improved, but the complexity of antibody engineering increases
Solution Approach 1:
The patent addresses this contradiction by providing fully human antibody sequences with specifically engineered CDR regions. The complete heavy chain variable region (SEQ ID NO: 4) and light chain variable region (SEQ ID NO: 8) sequences are disclosed, offering a ready-to-use solution that achieves high therapeutic effectiveness. This approach simplifies the overall engineering complexity by providing finalized, optimized sequences rather than requiring de novo engineering efforts.
Data Source
AI summary
An antibody specifically binding to TIGIT or an antigen-binding fragment thereof can effectively block the binding of TIGIT to a ligand thereof and release the inhibitory effect of the ligand of TIGIT on a downstream signal of TIGIT. The present invention further relates to a composition containing the antibody or antigen-binding fragment thereof, a nucleic acid coding the antibody or the antigen-binding fragment thereof, a host cell containing the nucleic acid, and a related use. In addition, the present invention also relates to treatment and diagnosis uses of the antibody or the antigen-binding fragment thereof.