MHC Class Ia Open Conformers for Immune Modulation
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Solution Overview
Problem
Current cancer treatments lack a unified approach to modulate the immune contexture effectively, as cancer cells evade immune detection through various mechanisms, and existing immunotherapies have limited efficacy due to the heterogeneous immune microenvironment in tumors.
Innovation Solution
The use of classical MHC class Ia open conformers (HLA-A, HLA-B, and HLA-C) as immunomodulatory agents, which interact with immunoregulatory receptors to modulate immune responses, including the use of HLA2-Fc fusion proteins to enhance anti-tumor immunity by increasing infiltration of beneficial leukocytes and reducing suppressive immune cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If classical MHC class Ia molecules present peptides to CD8+ T cells under normal physiological conditions, then immune response is initiated, but cancer cells evade immune detection through heterogeneous immune microenvironment
Solution Approach 1:
The patent inverts the conventional MHC class Ia structure by removing β2-microglobulin to generate open conformers that lack peptide-binding capability. This inverted structure enables direct interaction with immunoregulatory receptors (KIR, LILR, TIGIT) on immune cells, bypassing the traditional peptide presentation pathway that cancer cells exploit for evasion.
Solution Approach 2:
The patent fundamentally changes the structural parameter of MHC class Ia molecules by transitioning from the closed conformer state (with β2-microglobulin and peptide) to the open conformer state (without β2-microglobulin). This parameter change alters the molecular conformation to expose novel epitopes that directly engage immunoregulatory receptors, creating a new mode of immune activation that is not susceptible to conventional cancer evasion mechanisms.
2Reliability
If MHC-Ia molecules exist as heterotrimeric complexes with β2-microglobulin and peptide, then peptide presentation function is maintained, but interaction with immunoregulatory receptors is limited
Solution Approach 1:
The patent extracts β2-microglobulin from the MHC class Ia heterotrimeric complex, removing this essential component to generate open conformers. This extraction eliminates the steric and structural constraints that prevent direct receptor interaction, while the remaining heavy chain retains sufficient structural integrity to engage immunoregulatory receptors with high affinity.
Solution Approach 2:
The patent segments the MHC class Ia molecule into separate functional components: the heavy chain that interacts with immunoregulatory receptors and the β2-microglobulin that is removed. This segmentation allows the heavy chain to independently fulfill the immunoregulatory receptor binding function without being constrained by the complete heterotrimeric structure required for peptide presentation.
3Reliability
If existing immunotherapies target specific checkpoint molecules, then certain immune responses are enhanced, but overall immune contexture modulation remains limited
Solution Approach 1:
The patent creates a universal immunomodulatory agent (open conformer) that can interact with multiple families of immunoregulatory receptors including KIR, LILR, and TIGIT across different immune cell types. This multi-functional capability allows simultaneous modulation of various immune pathways (macrophage activation, NK cell function, T cell regulation) through a single therapeutic molecule, providing broad immune contexture modulation beyond single-checkpoint inhibition.
Data Source
AI summary
The invention relates to MHC-Ia open conformers as immunomodulatory agents, particularly in the treatment or prevention of cancer. The open conformer comprises or consists of a first and a second monomer, and each monomer comprises a HLA-heavy chain from the MHC-Ia molecules. The open conformer further comprises a protein stabilizing polypeptide sequence and optionally an amino acid linker. Further aspects of the invention provide combination medicaments comprising the MHC-Ia open conformers and immune checkpoint inhibitors. Furthermore, the invention relates to the use of MHC-Ia open conformers as immunomodulators, particularly in diseases where the interaction to diverse immunoregulatory receptors such as KIR3DL1, KIR3DL2, KIR3DL3, LILRB1, LILRB2, and PTPRJ modulates an immune response, and in diseases were the negative modulation of Tregs is a therapeutic strategy, e.g. infectious diseases.