Targeting CLEC2D-KLRB1 Pathway to Restore NK Cell Function in Glioblastoma
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Solution Overview
Problem
Current treatments for glioblastoma and other cancers are hindered by the inhibitory effects of KLRB1, a receptor expressed in immune cells, which suppresses the cytotoxic function of NK cells and cytokine secretion, and there is a need for effective methods to modulate its expression or activity to enhance immune response against tumors.
Innovation Solution
Administering agents that block the binding of CD161 to its ligands, reduce KLRB1 expression, or inhibit the binding of CLEC2D to receptors other than CD161, using antibodies, soluble proteins, or programmable nucleic acid modifying agents like CRISPR-Cas systems to target and modify KLRB1 expression in immune cells, particularly in the tumor microenvironment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If KLRB1 is expressed in immune cells, then immune cells can recognize tumor cells through CLEC2D binding, but the cytotoxic function of NK cells and cytokine secretion are inhibited
Solution Approach 1:
The patent uses antibodies as intermediary molecules that bind to KLRB1 or CLEC2D to block their interaction. These antibody intermediaries prevent the harmful inhibitory signaling while allowing or enhancing the beneficial tumor recognition function. The antibodies act as mediators that interfere with the pathological protein-protein interaction between KLRB1 and CLEC2D.
Solution Approach 2:
The patent employs programmable nucleic acid modifying agents (such as CRISPR-Cas systems) to change the expression level parameter of KLRB1 in immune cells. By reducing or eliminating KLRB1 expression through genetic modification, the inhibitory effect is removed while preserving or enhancing the immune cell's ability to recognize and attack tumor cells.
2Ease of manufacture
If current cancer treatments are used, then standard therapy protocols are maintained, but treatment effectiveness is reduced due to KLRB1-mediated immune suppression
Solution Approach 1:
The patent applies preliminary action by pre-treating immune cells with antibodies or genetically modifying them to reduce KLRB1 expression before administering them to the patient. This preliminary modification of the immune cells enhances their effectiveness against tumors, overcoming the immune suppression that would otherwise limit the success of standard cancer therapies.
Solution Approach 2:
The patent converts the harmful KLRB1-mediated immune suppression into a benefit by targeting and neutralizing KLRB1 function. By specifically blocking or reducing KLRB1 activity, the treatment transforms the immunosuppressive environment into an immunostimulatory one, enhancing the overall effectiveness of cancer therapy.
Data Source
AI summary
Provided are methods and compositions for treating cancer in a subject in need thereof. One of the top gene products in glioblastoma multiforme (GBM) is KLRB1 (also known as CD161), a C-type lectin protein that binds to CLEC2D. Binding of CLEC2D to the KLRB1 receptor inhibits the cytotoxic function of NK cells as well as cytokine secretion. KLRB1 is only expressed by small subpopulations of human blood T cells, and consequently little is known about the function of this receptor in T cells. However, preliminary data demonstrate that KLRB1 expression is induced in T cells within the GBM microenvironment. In an exemplary embodiment, a method is provided comprising administering an agent capable of blocking the interaction of KLRB1 with its ligand. The agent may comprise an antibody or fragment thereof, which may bind KLRB1 or CLEC2D.