Humanized Bi-specific Antibodies for Antigen-Specific T Cell Activation
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Solution Overview
Problem
Current methods for activating human T cells using murine OKT3 antibodies are immunogenic, leading to potential allergic reactions and immunogenicity concerns, necessitating the development of less immunogenic alternatives for clinical applications like cancer therapy.
Innovation Solution
The use of bi-specific antibodies (BsAbs) that comprise a tumor antigen binding site and a CD3 binding site, structured as single chain variable fragments (scFv), Fab, or IgG, to differentiate and proliferate T cells, avoiding murine OKT3 antibodies and reducing immunogenicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If murine OKT3 antibodies are used to activate human T cells, then T cell activation and proliferation can be achieved, but immunogenicity and allergic reactions occur
Solution Approach 1:
The patent changes the species origin parameter of the antibody from murine to human, creating humanized or fully human anti-CD3 antibodies that maintain T cell activation capability while eliminating immunogenicity. This parameter change resolves the contradiction by preserving the functional effect while removing the harmful immunogenic response.
Solution Approach 2:
The patent creates human versions of the murine OKT3 antibody by copying its structure and function but using human amino acid sequences. This allows the antibody to bind human CD3 and activate T cells without triggering immune rejection or allergic reactions, as the humanized structure is recognized as self by the human immune system.
2Productivity
If murine OKT3 antibodies are used for T cell activation, then clinical application can proceed, but murine protein fragments remain on T cell surfaces posing safety threats
Solution Approach 1:
The patent changes the compositional parameter of the antibody from containing murine protein sequences to containing only human protein sequences. This ensures that when the antibody binds to and activates T cells, no foreign murine fragments are transferred to the T cell surface, eliminating the safety threat while maintaining therapeutic productivity.
3Quantity of substance
If human T cells are activated using available methods, then T cell proliferation can be achieved, but the level remains insufficient for clinical applications
Solution Approach 1:
The patent combines multiple activation signals by using anti-CD3 antibodies that engage the T cell receptor complex, providing strong and sustained activation signals that drive robust T cell proliferation. This merged signaling approach achieves the high T cell numbers required for clinical applications while maintaining safety through humanized antibody construction.
Data Source
AI summary
Provided are methods of inducing differentiation and/or proliferation of T cells and uses thereof. In the present method, peripheral blood mononuclear cells (PBMCs) isolated from a subject are cultivated with bi-specific antibodies (BsAbs) in a culture medium so as to differentiate the PBMCs into the T cells. Each of the T cells has an anti-tumor antigen moiety and an anti-CD3 moiety on its surface. Also provided are methods and pharmaceutical kits for treating subjects suffering from cancers.