SPD-TNFSF Fusion Protein Multimerization for Targeted Tumor Activation
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current cancer therapies are often ineffective and toxic, and TNFSF ligands face challenges in achieving targeted activation and selective enhancement of T-cell responses due to limited binding selectivity and systemic toxicity, making them unsuitable for effective cancer treatment.
Innovation Solution
Development of a SPD-TNFSF fusion protein that includes a coiled-coil domain of surfactant protein-D fused with a TNF-superfamily ligand, allowing for efficient multimerization and optimal receptor clustering, enabling targeted tumor activation with reduced systemic toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If TNFSF ligands are used to stimulate T-cell responses, then antitumor immunity is enhanced, but systemic toxicity and off-target effects increase
Solution Approach 1:
The invention divides the TNFSF ligand into a modular structure with a collagen domain and a coiled-coil domain, allowing independent optimization of each component's function. The collagen domain provides structural stability and binding affinity, while the coiled-coil domain enables controlled multimerization, thereby reducing systemic toxicity while maintaining antitumor immunity.
Solution Approach 2:
The invention introduces tissue-specific promoters and targeting sequences that confer local activity to the TNFSF ligand expression. This ensures that the ligand is expressed primarily in the tumor microenvironment rather than systemically, thereby enhancing antitumor immunity locally while minimizing systemic toxicity.
2Adaptability or versatility
If TNFSF ligands are administered systemically, then T-cell activation is achieved, but binding selectivity and targeted activation are limited
Solution Approach 1:
The invention employs asymmetric molecular structures with specific collagen and coiled-coil domain arrangements that create directional binding preferences. This asymmetric design enables the ligand to selectively bind to tumor-associated receptors while avoiding normal tissue receptors, thereby improving binding selectivity while maintaining broad T-cell activation capability.
Solution Approach 2:
The invention introduces a targeting peptide or antibody fragment as an intermediary component that bridges the TNFSF ligand to tumor cells. This intermediary enhances binding selectivity by mediating specific interaction with tumor markers, while the ligand continues to provide broad T-cell activation through its receptor engagement.
3Power
If multimeric TNFSF ligands are used, then receptor clustering and signaling efficiency are improved, but molecular size and diffusion capability are reduced
Solution Approach 1:
The invention employs dynamic assembly mechanisms where the coiled-coil domain enables reversible multimerization of the TNFSF ligand. This dynamic structure allows the ligand to form multimers for enhanced signaling efficiency while maintaining the capability to dissociate and diffuse through tissue, thereby balancing signaling power with diffusion capability.
Solution Approach 2:
The invention optimizes the molecular weight and structural parameters of the TNFSF ligand by adjusting the collagen and coiled-coil domain configurations. This parameter optimization enables the ligand to achieve adequate multimerization for signaling efficiency while maintaining sufficient size for tissue diffusion and penetration.
Data Source
AI summary
The disclosure is in the field of immunology and oncology, especially for treating, preventing, or inhibiting proliferative diseases, particularly cancer, infectious diseases and disorders associated with dysfunction of TNF cytokines. The disclosure relates to a novel SPD-TNFSF fusion protein including a TNF-superfamily (TNFSF) ligand, or receptor binding domain thereof, fused to a coiled-coil domain of surfactant protein-D (SPD). Also provided a trimeric or multimeric fusion protein including a plurality of SPD-TNFSF fusion proteins. The disclosure also provides an expression vector as mRNA, plasmid or virus including an isolated nucleotide sequence encoding the SPD-TNFSF fusion protein and a cell or a pharmaceutical composition including thereof.