Humanized TIGIT Animal Model for Accurate Antibody Screening
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Solution Overview
Problem
Current cancer drug development methods, particularly for immunological checkpoints, face challenges due to the inability of traditional in vitro and in vivo screening approaches to accurately replicate the human body's tumor microenvironment, leading to high failure rates and discrepancies between animal and clinical trial results.
Innovation Solution
The development of a genetically modified animal model that expresses human or chimeric T cell immunoreceptor with Ig and ITIM domains (TIGIT), allowing for the study of TIGIT function and the evaluation of anti-TIGIT antibodies in a human-relevant context, including the use of TIGIT gene knockout mice and combination therapies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If traditional in vitro and in vivo screening approaches are used, then drug development can proceed with conventional methods, but the results cannot accurately reflect human disease state and show high failure rates in clinical trials
Solution Approach 1:
The patent applies parameter changes by replacing the animal TIGIT gene with the human TIGIT gene in the animal model. This genetic parameter substitution creates a humanized animal model that expresses human TIGIT protein, enabling accurate screening of anti-human TIGIT antibodies and reflecting human disease state, thereby improving both measurement precision and reducing clinical trial failure rates
Solution Approach 2:
The patent creates a copy of the human TIGIT gene and introduces it into the animal genome to replace the endogenous animal TIGIT gene. This copying approach generates a humanized animal model that replicates human TIGIT biology, allowing for accurate preclinical evaluation of human therapeutics and reducing the discrepancy between animal studies and clinical outcomes
2Ease of operation
If conventional experimental animals are used for in vivo pharmacological tests, then animal experiments can be conducted easily, but the test results cannot reflect the real disease state and identification and interaction at the targeting sites
Solution Approach 1:
The patent modifies the genetic parameter of the animal model by substituting the animal TIGIT gene with the human TIGIT gene. This creates a humanized animal model that maintains the ease of animal experimentation while accurately reflecting human disease state, protein identification, and antibody-drug interactions at the targeting sites
Solution Approach 2:
The humanized animal model serves as an intermediary system between conventional animal models and human clinical trials. By expressing human TIGIT protein in an animal organism, it provides a bridge that enables accurate preclinical testing of human therapeutics while maintaining the operational advantages of animal experimentation
Data Source
AI summary
The present disclosure relates to the genetically modified non-human animals that express a human or chimeric TIGIT (e.g., humanized TIGIT), and methods of use thereof.