HVEM Cis Complexes Inhibit T Cell Activation
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current understanding of cosignaling pathways, particularly involving HVEM and its ligands, is limited, leading to unsafe therapeutic applications and inadequate management of autoimmune diseases like rheumatoid arthritis and psoriasis, while other diseases such as lupus erythematosus remain unresponsive.
Innovation Solution
The formation of HVEM cis complexes with BTLA and CD160, which are distinct from trans complexes, acts as a molecular switch to inhibit signaling, providing a mechanism for maintaining T cells in a resting state and limiting immune responses, and the use of specific antibodies that bind preferentially to these cis complexes to modulate immune activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If HVEM trans complexes with ligands (LIGHT, BTLA, CD160) are engaged to activate immune responses, then immune activation and inflammation are enhanced, but this leads to harmful autoimmune responses and unsafe therapeutic applications
Solution Approach 1:
The patent segments the HVEM signaling system into two distinct functional forms: cis complexes (HVEM bound to BTLA or CD160 on the same cell) that inhibit signaling, and trans complexes (HVEM bound to LIGHT or BTLA on different cells) that activate signaling. This segmentation allows selective modulation of immune activation versus autoimmune responses by targeting specific complex configurations with antibodies or soluble ligands.
Solution Approach 2:
The patent changes the binding parameters of HVEM by introducing soluble ligands (soluble LIGHT, soluble BTLA) and engineered antibodies that can selectively bind to either cis or trans complexes. This parameter change enables control over the equilibrium between active and inactive states of the HVEM signaling system, allowing therapeutic modulation without causing harmful autoimmune responses.
2Adaptability or versatility
If cosignaling pathways are manipulated to treat autoimmune diseases like rheumatoid arthritis and psoriasis, then these diseases show improvement, but other diseases like lupus erythematosus remain unresponsive
Solution Approach 1:
The patent applies local quality by creating therapeutics with different specificities: some antibodies and soluble ligands preferentially bind cis complexes to inhibit signaling (suitable for lupus erythematosus), while others bind trans complexes to enhance activation (suitable for rheumatoid arthritis and psoriasis). This local differentiation of therapeutic action allows customization of treatment based on the specific disease context and patient needs.
3Reliability
If HVEM-BTLA trans signaling is activated to promote inflammation and immune responses, then immune homeostasis is maintained, but this prevents treatment of diseases requiring immune suppression
Solution Approach 1:
The patent introduces soluble ligands (soluble BTLA-Fc, soluble LIGHT) and engineered antibodies as intermediaries that can selectively modulate HVEM signaling. These intermediaries bind to HVEM or its partners with different affinities and specificities, acting as controllable switches that can tip the balance between activation and inhibition based on therapeutic needs, thereby resolving the contradiction between maintaining homeostasis and suppressing inflammation.
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 HVEM cis complexes effectively inhibit activation of T cells and antigen-presenting cells, reducing inflammation and autoimmune responses, offering a targeted approach to treat autoimmune diseases and inflammatory conditions.
Implementation Method 1
BTLA and HVEM form a 'cis' complex, and CD160 and HVEM form a 'cis' complex. This HVEM-BTLA 'cis' complex competitively inhibits trans signaling by all cellular ligands of HVEM
Implementation Method 2
The invention also provides antibodies that bind to a cis complex. In one embodiment, an antibody binds to HVEM/BTLA cis complex
Implementation Method 3
The HVEM cis complexes effectively inhibit activation of T cells and antigen-presenting cells, reducing inflammation and autoimmune responses
Data Source
AI summary
The invention provides HVEM cis complexes which include, for example, HVEM/BTLA, HVEM/CD160 and HVEM/gD cis complexes. The invention provides ligands and agents that bind to HVEM cis complexes, such as antibodies. The invention further provides methods of use of the HVEM cis complexes, and the ligands and agents (e.g., antibodies) that bind to the HVEM cis complexes.