DLL3/CD3 Multi-Specific Binding Proteins for Targeted T-Cell Redirection
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Solution Overview
Problem
Current therapies for DLL3-expressing cancers, such as small cell lung cancer (SCLC) and glioblastoma, lack targeted and effective treatments due to low cell surface expression of DLL3 and high resistance to chemotherapy, with existing approaches like antibody drug conjugates (ADCs) facing limitations and off-target toxicities.
Innovation Solution
Development of multi-specific binding proteins that simultaneously bind to DLL3 on tumor cells and CD3 on T cells, forming a cytolytic synapse to redirect T cell activity selectively to targeted tumor cells, enhancing therapeutic efficacy and safety.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antibody drug conjugates (ADCs) are used to target DLL3, then targeted therapy is provided, but off-target toxicities occur due to low cell surface expression of DLL3 and linker instability
Solution Approach 1:
The invention divides the therapeutic approach into two separate binding functions within a single protein: one arm specifically targets DLL3 on tumor cells while the other arm engages CD3 on T cells. This segmentation allows selective redirection of T cell cytotoxicity to DLL3-positive targets, improving reliability of targeted therapy while reducing off-target toxicities by avoiding unstable linkers and non-specific drug delivery
Solution Approach 2:
The multi-specific binding protein acts as an intermediary molecule that bridges T cells and DLL3-expressing tumor cells. By simultaneously binding to CD3 on T cells and DLL3 on tumor cells, it forms a stable cytolytic synapse without requiring unstable chemical linkers, thereby achieving reliable targeted therapy with reduced off-target effects
2Productivity
If chemotherapy is used to treat DLL3-expressing cancers, then initial response rate is high, but patients quickly relapse with chemo-resistant disease
Solution Approach 1:
The invention harnesses the patient's own T cell immune system to perform the therapeutic function. The multi-specific binding protein redirects endogenous T cells to recognize and kill DLL3-expressing tumor cells, creating a self-sustaining immune response that can adapt and overcome resistance mechanisms, thereby improving long-term efficacy compared to chemotherapy
Solution Approach 2:
The invention changes the therapeutic mechanism from chemical cytotoxicity (chemotherapy) to immune-mediated cytotoxicity (T cell engagement). This parameter change from chemotherapy to immunotherapy allows the treatment to bypass chemoresistance pathways while maintaining high initial response rates and achieving durable long-term remission
3Reliability
If multi-specific binding proteins are developed to simultaneously bind DLL3 and CD3, then specificity and therapeutic efficacy are improved, but protein structure complexity increases
Solution Approach 1:
The invention merges two separate antibody binding functions into a single multi-specific binding protein molecule. By combining the DLL3-binding domain and CD3-binding domain in one protein structure, it achieves high specificity for targeted T cell redirection while simplifying the overall therapeutic approach compared to using separate antibodies or ADCs
Solution Approach 2:
The multi-specific binding protein performs multiple functions simultaneously: it binds to DLL3 on tumor cells, engages CD3 on T cells, and facilitates formation of the cytolytic synapse. This multi-functionality within a single protein molecule improves specificity and therapeutic efficacy without requiring multiple separate therapeutic agents
Data Source
AI summary
The present invention relates to novel DLL3/CD3 binding proteins. The invention also relates to nucleic acids encoding such proteins; to methods for preparing such proteins; to host cells expressing or capable of expressing such proteins; to compositions comprising such proteins; and to uses of such proteins or such compositions, in particular for therapeutic purposes in the field of cancer diseases.