Trifunctional Molecule for CD19 and CD3 Binding
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Solution Overview
Problem
Current bispecific antibodies targeting CD19, such as anti-CD19/anti-CD3 BiTE, have low bioavailability and require continuous intravenous injection due to their small molecular weight and neurotoxicity, while CAR-T technology is complex and carries risks of cytokine storms, making them inefficient and risky for cancer treatment.
Innovation Solution
A trifunctional molecule is developed that binds to CD19, activates CD3, and activates CD28, produced via eukaryotic cell expression with a simple purification process, eliminating the need for separate expression and purification of bispecific antibodies and avoiding viral transduction, thus enhancing T cell activation and reducing side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If anti-CD19/anti-CD3 BiTE bisspecific antibody is used, then T cell activation and tumor cell killing ability is improved, but bioavailability is low and neurotoxicity occurs due to small molecular weight
Solution Approach 1:
The patent combines the anti-CD19 single-chain antibody variable fragment, anti-CD3 single-chain antibody variable fragment, and Fc region into a single trifunctional molecule structure. This merging increases the molecular weight and improves bioavailability while reducing neurotoxicity, while maintaining the T cell activation and tumor cell killing abilities provided by the anti-CD19 and anti-CD3 binding domains.
Solution Approach 2:
The trifunctional molecule uses a composite structure combining different antibody fragments (single-chain variable fragments and Fc region) to create a molecule with optimized properties. The Fc region addition not only increases molecular weight but also provides additional functional benefits including extended half-life and reduced neurotoxicity.
2Reliability
If CAR-T technology is used, then T cell activation and tumor elimination efficacy is improved, but treatment complexity and risk of cytokine storms increase
Solution Approach 1:
The patent extracts the essential T cell activation functions from the complex CAR-T cell therapy and concentrates them into a single administerable trifunctional molecule. This eliminates the need for viral transduction, in vitro expansion, and reinfusion steps, while maintaining effective T cell activation and tumor elimination capabilities.
Solution Approach 2:
The trifunctional molecule acts as an intermediary that bridges the interaction between T cells and tumor cells, providing the necessary activation signals without requiring genetic modification of T cells. The molecule mediates the complex immune activation process in a controlled, externally administerable form.
3Reliability
If two bispecific antibodies (anti-CD19/anti-CD3 and anti-CD19/anti-CD28) are used in combination, then T cell activation is enhanced, but manufacturing complexity and cost increase
Solution Approach 1:
The patent merges the functions of two separate bisspecific antibodies (anti-CD19/anti-CD3 and anti-CD19/anti-CD28) into a single trifunctional molecule that simultaneously binds CD19, CD3, and CD28. This consolidation simplifies the manufacturing process to a single expression and purification step, reducing complexity and cost while maintaining enhanced T cell activation through both CD3 and CD28 co-stimulation.
Solution Approach 2:
The trifunctional molecule is designed with multi-functionality, simultaneously providing tumor targeting (anti-CD19), primary T cell activation (anti-CD3), and co-stimulation (anti-CD28) in one molecule. This universal design eliminates the need for multiple separate antibody products and their associated manufacturing complexities.
Data Source
AI summary
This disclosure belongs to the field of biomedical technology, and particularly refers to a trifunctional molecule and the application thereof. The structure of the trifunctional molecule includes a first functional domain, a second functional domain and a third functional domain. These domains are capable of simultaneously binding to CD19, CD3, and T cell positive (negative) costimulatory factors, thereby producing the first and second signal required for T cell activation. The trifunctional molecule is a recombinant protein peptide chain, which can be produced by a eukaryotic cell expression system. The product has a single structure, simple purification process, high protein yield, and preparation process and product stability. The trifunctional molecule is superior to the anti-CD19/anti-CD3 BiTE bispecific antibody in killing CD19-positive target cells. Compared with the CAR-T technology targeting CD19, the trifunctional molecule is more convenient to use, the dose is controllable, and the side effects of CAR-T are avoided.