BiTE-Sialidase Fusion Proteins for Solid Tumor Immune Synapse Formation
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Solution Overview
Problem
Bispecific T cell engagers (BiTEs) face limited penetration into tumor tissue and are hindered by immunosuppressive tumor microenvironments, leading to T cell exhaustion and poor tumor control in treating solid tumors.
Innovation Solution
Development of fusion proteins combining a bispecific molecule with a sialidase to enhance tumor cell susceptibility to killing by selectively removing sialoglycans at the T cell-target tumor cell interface, promoting stronger immunological synapse formation and overcoming inhibitory sialoglycan-Siglec signaling.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If BiTE molecules are used to engage T cells and target tumor cells, then T cell activation and tumor cell killing are enhanced, but penetration into tumor tissue is limited and T cell exhaustion occurs in the immunosuppressive tumor microenvironment
Solution Approach 1:
The patent combines a BiTE molecule with a sialidase enzyme into a single fusion protein. The BiTE portion engages T cells and targets tumor cells, while the sialidase portion removes sialoglycans from the tumor cell surface. This merging of two functional components into one molecule allows simultaneous T cell engagement and modulation of the tumor microenvironment to prevent T cell exhaustion.
Solution Approach 2:
The fusion protein represents a composite molecular structure combining an antibody-derived BiTE molecule with an enzymatic sialidase component. This composite structure integrates the immune-engaging function of the BiTE with the microenvironment-modulating function of the sialidase, creating a molecule with dual functionality that addresses both T cell activation and immunosuppression.
2Productivity
If BiTE molecules are used to target tumor cells, then tumor cell susceptibility to killing is increased, but penetration into tumor tissue remains limited
Solution Approach 1:
The fusion protein merges the BiTE molecule with a sialidase enzyme, allowing the single molecule to simultaneously engage T cells, target tumor cells, and modify the tumor cell surface by removing sialoglycans. This combination enhances tumor cell susceptibility to killing while the molecule's small size facilitates penetration into tumor tissue.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The BiTE-sialidase fusion proteins demonstrate enhanced tumor cell cytolysis and T cell activation, showing improved efficacy in killing tumor cells both in vitro and in vivo, particularly targeting HER2 and CD19 antigens, with superior performance compared to BiTEs alone.
Implementation Method 1
a sialidase or enzymatic fragment thereof... selectively removing sialoglycans at the T cell-target tumor cell interface
Data Source
AI summary
The invention provides fusion molecules that contain a sialidase and a bispecific molecule that engages an immune cell (e.g., T cell or NK cell) and a target cell underlying a disease. Related polynucleotides, vectors and host cells are also described herein. The invention further provides therapeutic applications of the sialidase fusions in treating cancer.