Multi-Specific DARPin T-Cell Engagers for AML
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Solution Overview
Problem
Current treatments for acute myeloid leukemia (AML) face challenges such as limited target specificity, severe side effects like cytokine release syndrome, and development of tumor resistance due to downregulation of target antigens, necessitating new therapeutic approaches that can effectively target multiple tumor-associated antigens while minimizing immune system hyperstimulation.
Innovation Solution
Development of recombinant proteins comprising a binding agent specific to immune cells and multiple binding agents specific to different tumor-associated antigens, such as CD3, CD33, CD123, and CD70, which can bind simultaneously to these targets, enhancing tumor specificity and potency while reducing cytokine release and resistance development.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antibody-based T cell engagers are used to target tumor cells, then T cell cytotoxicity against tumor cells is achieved, but cytokine release syndrome and on-target/off-tumor toxicities occur
Solution Approach 1:
The patent combines multiple tumor antigen-specific binding domains (anti-CD33, anti-CD123, anti-CD70) into a single T cell engager molecule. This multi-specific design requires simultaneous engagement of multiple antigens on tumor cells plus CD3 on T cells, thereby increasing target specificity and reducing off-tumor toxicity while maintaining effective T cell activation against tumor cells.
Solution Approach 2:
The patent creates different binding domains with specific local functions within the single molecule: each antigen-specific domain (CD33, CD123, CD70) is optimized to bind its respective tumor antigen with appropriate affinity, while the CD3-binding domain is optimized for T cell engagement. This local optimization of binding characteristics reduces systemic immune activation and cytokine release syndrome.
2Force
If high affinity binding to CD3 is achieved in T cell engagers, then strong T cell activation occurs, but efficiency of T cell activation and tumor cell killing decreases
Solution Approach 1:
The patent employs multiple antigen-specific binding domains (CD33, CD123, CD70) that collectively provide the necessary binding force to tumor cells. This distributed binding approach prevents any single domain from binding with excessively high affinity to CD3, which would cause harmful hyperactivation. The combined effect of multiple domains achieves sufficient activation without the negative effects of overly strong single-domain binding.
3Device complexity
If single tumor antigen targets are used in T cell engagers, then simplified design is achieved, but tumor resistance develops due to target downregulation
Solution Approach 1:
The patent designs a multi-specific T cell engager that can simultaneously recognize and bind to multiple different tumor antigens (CD33, CD123, CD70) on the same tumor cell. This multi-functional design ensures that the therapy remains effective even if tumor cells downregulate or lose expression of any single antigen, as the engager can still engage tumor cells through alternative antigens, preventing escape and resistance.
Data Source
AI summary
The present invention relates to recombinant multi-specific proteins comprising binding agents with binding specificity for different targets, such as, e.g. CD3, CD33, CD123 and CD70. In addition, the invention relates to nucleic acids encoding such multi-specific proteins, pharmaceutical compositions comprising such proteins or nucleic acids, and the use of such binding proteins, nucleic acids or pharmaceutical compositions in methods for treating or diagnosing diseases, such as cancer, e.g. acute myeloid leukaemia (AML), in a mammal, including a human.