KIR-binding agents for NK cell activation
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Solution Overview
Problem
Current therapeutic agents fail to effectively activate Natural Killer (NK) cells by targeting alternative mechanisms beyond blocking the interaction between Killer Ig-like Receptor (KIR) and HLA class I molecules, limiting their ability to enhance NK cell cytotoxicity.
Innovation Solution
Development of novel agents that bind to inhibitory KIRs, reducing their dimerization and clustering, thereby potentiating NK cell activity without interfering with KIR-HLA interactions, using cross-reactive antibodies or antibody fragments that target specific domains on KIRs.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If therapeutic agents block the interaction between KIR and HLA class I molecules to activate NK cells, then NK cell cytotoxicity is enhanced, but the agents cannot effectively activate NK cells through alternative mechanisms
Solution Approach 1:
The patent segments the KIR receptor structure into distinct functional domains: the HLA-binding domain and the dimerization/clustering domain. By targeting the dimerization domain with specific antibodies (such as anti-KIR2DL1 antibodies), the invention activates NK cells through a mechanism distinct from HLA blocking, thereby providing mechanism diversity while maintaining reliable NK cell activation.
Solution Approach 2:
The patent introduces antibodies as intermediary molecules that bind to KIR receptors and mediate NK cell activation. These antibodies act as intermediaries between the therapeutic agent and the KIR-HLA interaction system, enabling activation through alternative pathways (such as preventing dimerization) while the KIR-HLA interaction mechanism remains intact for other functions.
2Productivity
If agents target KIR-HLA interactions to enhance NK cell activity, then NK cell cytotoxicity increases, but agents cannot bind to alternative determinants on KIR
Solution Approach 1:
The patent applies local quality by directing antibodies to specific local regions on the KIR receptor structure. Rather than targeting the HLA-binding site, the antibodies bind to distinct determinants on the KIR extracellular domains (such as domains 1 or 2), locally modulating KIR function to prevent dimerization while leaving the HLA-binding capability intact. This enables productive NK cell activation through multiple targetable regions on KIR.
3Reliability
If current therapeutic strategies rely solely on blocking KIR-HLA interactions, then NK cell activation is limited, but no alternative activation pathways are utilized
Solution Approach 1:
The patent赋予KIR receptors multi-functionality by demonstrating that they can be targeted through multiple mechanisms: traditional HLA blocking and the novel approach of preventing dimerization/clustering. The KIR-HLA interaction system serves universal functions including both ligand binding and dimerization-mediated regulation, allowing therapeutic agents to activate NK cells through either pathway, thereby ensuring reliable activation with pathway diversity.
Data Source
AI summary
The present invention relates to agents and methods that are capable of augmenting NK-mediated killing of target cells by reducing inhibitory KIR signalling without reducing the binding of KIR to HLA-C. As described herein, transduction of negative signaling via KIR, upon binding of KIR to its HLA class I ligand, can involve a ligand-binding induced, conformational reorientation of the KIR molecules allowing interactions to form between adjacent KIRs in specific domains, leading to accelerated clustering. Methods and agents such as monoclonal antibodies for reducing KIR-mediated inhibition of NK cell cytotoxicity without reducing or blocking HLA-binding by, e.g., reducing or blocking dimerization of KIR, are provided.