HHLA2 Binding Agents for Dual KIR3DL3/TMIGD2 Modulation
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Solution Overview
Problem
Current immune checkpoint inhibitors vary in expression and interaction with natural binding partners between patients, limiting their effectiveness in modulating immune responses for treating diseases like cancer.
Innovation Solution
Development of HHLA2 binding agents that inhibit HHLA2 binding to KIR3DL3 and enhance binding to TMIGD2, modulating immune responses through allosteric changes and conformational alterations in HHLA2, thereby targeting immune checkpoints for enhanced T-cell activation and cytotoxic activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current immune checkpoint inhibitors are used to modulate immune responses, then immune response modulation is achieved in some patients, but effectiveness varies between patients due to variable immune checkpoint expression and interactions with natural binding partners
Solution Approach 1:
The patent uses HHLA2 as an intermediary target molecule that bridges the gap between variable immune checkpoint expression and consistent therapeutic effect. By developing binding agents that specifically target HHLA2 (which is consistently expressed across different patient populations) rather than directly targeting variable checkpoints like PD-1 or CTLA-4, the invention achieves reliable immune response modulation regardless of patient-specific checkpoint expression variations. The HHLA2 binding agent acts as a mediator that restores balanced immune signaling by simultaneously engaging both stimulatory (TMIGD2) and inhibitory (KIR3DL3) receptors.
2Object-generated harmful factors
If HHLA2 binding agents inhibit HHLA2 binding to KIR3DL3, then immune response inhibition is reduced, but selective inhibition without enhancing stimulatory pathways is difficult to achieve
Solution Approach 1:
The patent employs parameter changes by developing binding agents with specific affinity characteristics that enable differential modulation of HHLA2 interactions. The binding agents are engineered to have optimal affinity parameters that allow them to induce conformational changes in HHLA2, shifting its binding preference from the inhibitory KIR3DL3 receptor to the stimulatory TMIGD2 receptor. This parameter optimization enables the same binding agent to simultaneously achieve inhibition of the harmful HHLA2-KIR3DL3 interaction while enhancing the beneficial HHLA2-TMIGD2 interaction.
Solution Approach 2:
The invention utilizes dynamics by designing binding agents that induce conformational changes in HHLA2, making the system dynamic rather than static. The binding agents do not simply block one interaction; they actively reshape HHLA2's conformational state, enabling it to dynamically switch from an inhibitory binding mode (with KIR3DL3) to a stimulatory binding mode (with TMIGD2). This dynamic approach allows the system to adapt and achieve dual functionality through a single therapeutic agent.
Data Source
AI summary
The present disclosure pertains to HHLA2 binding agents with novel activity and uses thereof.