TRBC-Targeting Multifunctional Molecules for Localized Immune Engagement
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Solution Overview
Problem
Current treatments for T cell lymphomas (TCLs) are inadequate, and there is a need for improved compositions and therapies that target these lymphomas with reduced systemic toxicity and enhanced immune response.
Innovation Solution
Development of multispecific or multifunctional molecules that bind to T cell receptor beta chain constant domains (TRBC1 or TRBC2) and engage immune cells like NK cells, altering the tumor stroma to enhance localized immune responses against T cell lymphomas, while sparing non-cancerous T cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If systemic immunosuppression is used to treat T cell lymphomas, then lymphoma cells are targeted, but non-cancerous T cells are also affected causing deleterious effects
Solution Approach 1:
The patent applies local quality by designing molecules with dual specificity: one binding domain targets TRBC1 or TRBC2 on lymphoma cells, while the other binds to activating receptors on immune effector cells. This localized dual-targeting approach concentrates the immune response specifically at the tumor site rather than systemically, thereby eliminating lymphoma cells while preserving non-cancerous T cell function throughout the body.
Solution Approach 2:
The patent employs intermediary molecules (multispecific antibodies or TCRs) that mediate between the tumor antigen (TRBC1/TRBC2) and immune effector cells. These intermediary molecules act as bridges that selectively recruit and activate immune cells only at locations where TRBC-expressing lymphoma cells are present, preventing widespread activation and toxicity to healthy T cells.
2Reliability
If conventional chemotherapy is used for T cell lymphomas, then lymphoma cells are targeted, but treatment is inadequate and lacks selectivity
Solution Approach 1:
The patent implements local quality through molecules engineered with two distinct binding specificities: one for TRBC1 or TRBC2 (markers on lymphoma cells) and another for activating receptors on immune effector cells. This dual-specificity design ensures that the therapeutic effect is localized precisely to TRBC-expressing malignant T cells, providing both effectiveness and selectivity that conventional chemotherapy lacks.
3Reliability
If all T cells are targeted systemically, then lymphoma cells are eliminated, but non-cancerous T cells are also destroyed reducing immune function
Solution Approach 1:
The patent uses intermediary multispecific molecules that selectively bridge TRBC-expressing lymphoma cells with immune effector cells. These intermediaries ensure that immune activation and cell depletion occur only at sites where TRBC is present on malignant cells, leaving non-cancerous T cells untouched and preserving their essential immune functions.
Solution Approach 2:
The patent applies local quality by designing molecules that concentrate immune activation specifically at tumor sites expressing TRBC1 or TRBC2. This localized action spares non-cancerous T cells throughout the rest of the body, maintaining their critical roles in immune surveillance and function while still achieving effective depletion of malignant T cells.
Data Source
AI summary
Multifunctional molecules that include i) an antigen binding domain that binds to a T cell receptor beta chain constant domain 1 or T cell receptor beta chain constant domain 2; and one, two or all of: (ii) an immune cell engager (e.g., chosen from an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager); (iii) a cytokine molecule or cytokine inhibitor molecule; (iv) a death receptor signal enhancer; and/or (v) a stromal modifying moiety are disclosed. Additionally disclosed are nucleic acids encoding the same, methods of producing the aforesaid molecules, and methods of treating a cancer using the aforesaid molecules.