Humanized TIGIT Antibody Specificity and Affinity Optimization
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Solution Overview
Problem
Current therapies lack effective TIGIT antibodies suitable for clinical use, despite the potential of TIGIT as a target for immunotherapy, particularly in tumor treatment, due to the need for high specificity and affinity.
Innovation Solution
Development of monoclonal antibodies and antigen-binding fragments that specifically bind to the extracellular region of TIGIT with high affinity, utilizing specific heavy and light chain variable region sequences and variants, including chimeric and humanized antibodies to enhance specificity and reduce immunogenicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing TIGIT antibody candidates are used, then some anti-tumor effects are observed in animal models, but the antibodies lack high specificity and affinity required for clinical use
Solution Approach 1:
The patent applies parameter changes by systematically optimizing the antibody sequence parameters (heavy chain and light chain variable regions) to achieve both high specificity and high affinity binding to TIGIT. This involves identifying and modifying specific amino acid sequences in the CDR regions to enhance binding characteristics while maintaining specificity for the TIGIT target.
Solution Approach 2:
The patent uses copying by creating multiple antibody variants through sequence duplication and modification. Multiple heavy chain and light chain variable region sequences are generated and tested to identify the optimal combination that achieves the desired specificity and affinity, effectively copying and refining the binding interface.
2Reliability
If murine antibodies are used for TIGIT blocking, then anti-tumor effects are achieved, but immunogenicity increases and clinical applicability decreases
Solution Approach 1:
The patent applies composite materials by creating chimeric antibodies that combine murine variable regions (providing anti-tumor activity) with human constant regions (reducing immunogenicity). This composite structure integrates the beneficial properties of both murine and human antibody components, achieving therapeutic efficacy while minimizing immune reactions.
Solution Approach 2:
The patent applies local quality by selectively applying murine sequences only in the variable regions where anti-tumor activity is needed, while using human sequences in the constant regions to minimize immunogenicity. This localized approach allows different parts of the antibody to have different properties optimized for their specific functions.
3Productivity
If TIGIT blocking antibodies are developed, then T cell activation is enhanced, but off-target effects and safety issues may arise
Solution Approach 1:
The patent applies mechanics substitution by replacing non-specific immune activation mechanisms with targeted molecular binding. The antibody specifically binds to the TIGIT receptor through complementary determining regions, providing precise molecular recognition that activates T cells only when TIGIT is present, thereby reducing off-target effects.
Solution Approach 2:
The patent uses an intermediary approach where the TIGIT antibody acts as a mediator between the immune system and the tumor. The antibody specifically engages TIGIT on tumor cells and immune cells, facilitating targeted T cell activation only at the tumor site rather than system-wide activation, thus reducing harmful off-target effects.
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 strong binding affinity to TIGIT, promoting immune activation and potentially offering therapeutic benefits in treating T cell dysfunction disorders, including cancers and infectious diseases by enhancing NK cell and T cell activity.
Implementation Method 1
monoclonal antibodies or antigen-binding fragments that specifically bind to the amino acid sequence or three-dimensional structure of the extracellular region of TIGIT
Data Source
AI summary
A TIGIT antibody, an antigen-binding fragment thereof, and a medical use thereof. The present invention relates to a murine antibody, a chimeric antibody, and a humanized antibody comprising a CDR region of the TIGIT antibody, and a pharmaceutical composition comprising the TIGIT antibody and the antigen-binding fragment thereof, and a use thereof as a medicament. In particular, the present invention also relates to a use of a humanized TIGIT antibody for preparing a medicament for the treatment of TIGIT-associated diseases or conditions.