PD-1 and LILRB1/2 Checkpoint Combination for Refractory Cancer
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Solution Overview
Problem
Existing cancer treatments using PD-1 pathway inhibitors are ineffective for over 70% of patients, as additional inhibitory mechanisms within the tumor microenvironment inhibit CD8+ T cell activity, necessitating improved therapeutic strategies.
Innovation Solution
Combining antibodies or antigen-binding fragments that target PD-1, PD-L1, PD-L2 with antibodies or antigen-binding fragments that target LILRB1, LILRB2, or HLA-G, or using siRNA to reduce HLA-G expression, to enhance IFN-γ expression and CD8+ T-cell cytotoxicity in cancer patients.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If PD-1/PD-L1 inhibitor monotherapy is used, then treatment simplicity is maintained, but efficacy is limited in over 70% of patients due to additional inhibitory mechanisms
Solution Approach 1:
The patent combines PD-1/PD-L1 pathway inhibitors with LILRB1/2 pathway inhibitors into a single therapeutic regimen. This merging of two different immune checkpoint blockade mechanisms addresses the limitation of PD-1 monotherapy by simultaneously targeting multiple inhibitory pathways that suppress CD8+ T cell activity in the tumor microenvironment, thereby overcoming resistance in patients who do not respond to single-agent therapy.
2Reliability
If combination therapy targeting multiple immune pathways is implemented, then treatment efficacy is improved in refractory patients, but treatment complexity increases
Solution Approach 1:
The combination therapy is segmented into two distinct but complementary components: PD-1/PD-L1 pathway inhibitors and LILRB1/2 pathway inhibitors. Each component targets a specific immune checkpoint pathway, allowing for modular administration. This segmentation enables clinicians to tailor the combination approach to patient needs while maintaining clear dosing and administration protocols for each agent.
3Reliability
If additional inhibitory pathways are targeted, then CD8+ T cell activity is enhanced, but mechanism complexity increases
Solution Approach 1:
The LILRB1/2 pathway inhibitors serve as intermediary agents that specifically block the interaction between LILRB1/2 receptors on CD8+ T cells and their ligands (including HLA-G and other MHC class I molecules) on tumor cells. This intermediary blockade prevents the delivery of inhibitory signals to T cells, thereby enhancing T cell activation and cytotoxicity without directly manipulating the complex intracellular signaling networks within the T cells themselves.
Data Source
AI summary
This invention relates to combination therapies comprising a Programmed Death 1 receptor (PD-1) pathway inhibitor, and a Leukocyte Immunoglobulin Like Receptor B (LILRB) signaling inhibitor, and the use of the combination therapies for the treatment of cancer. The invention also relates to the treatment of cancer patients who are refractory to monotherapy with a PD-1 pathway inhibitor.