Combination Therapy Targeting PD-L2 and PD-1 for Dysbiosis Resistance
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Solution Overview
Problem
A significant fraction of cancer patients do not respond to or fail immune checkpoint blockade therapies, such as anti-PD1/PD-L1 treatments, due to dysbiosis altering the gastrointestinal microbiota, which impairs the effectiveness of these therapies by increasing PD-L2 expression in tumor cells or antigen-presenting cells.
Innovation Solution
Administering a combination of a first agent that blocks or disrupts PD-L2 or RGMb and a second agent that blocks or disrupts PD-L1 or PD-1, specifically using antibodies, fusion proteins, or nucleic acid molecules to target these proteins, to overcome the immunosuppressive effects of dysbiosis and enhance anti-tumor responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If immune checkpoint blockade therapy (anti-PD1/PD-L1) is administered to treat cancer, then anti-tumor response is improved, but treatment effectiveness deteriorates in patients with dysbiosis due to increased PD-L2 expression
Solution Approach 1:
The patent segments the immune checkpoint blockade into two separate targeting agents: one agent (e.g., anti-PD-1 or anti-PD-L1) targets the PD-1/PD-L1 pathway, while a second agent (e.g., anti-PD-L2) specifically targets the PD-L2 pathway. This segmentation allows simultaneous blockade of both pathways, overcoming the resistance mechanism where dysbiosis-induced PD-L2 expression renders single-agent PD-1/PD-L1 blockade ineffective.
Solution Approach 2:
The patent employs a composite therapeutic approach by combining two distinct antibody agents with different target specificities. The first agent targets PD-1 or PD-L1, while the second agent targets PD-L2. This composite strategy creates a synergistic effect where the combination therapy achieves superior anti-tumor efficacy compared to either agent alone, particularly in patients with dysbiosis who would otherwise respond poorly to monotherapy.
2Reliability
If combination therapy targeting both PD-L2 and PD-L1/PD-1 is administered, then anti-tumor response is improved, but device complexity increases
Solution Approach 1:
The patent merges two separate therapeutic agents into a combination regimen. The first agent (anti-PD-1 or anti-PD-L1) and the second agent (anti-PD-L2) are administered together, either simultaneously or in a coordinated sequence. This merging of therapies creates a unified treatment approach that addresses multiple immune checkpoint pathways, thereby overcoming the limitations of single-agent therapy while managing the complexity through established combination therapy protocols.
3Reliability
If dysbiosis is present in the patient, then immune checkpoint blockade therapy fails, but the underlying cause (altered microbiota) is not directly addressable by the therapy
Solution Approach 1:
The patent applies preliminary anti-action by proactively targeting the PD-L2 pathway in addition to PD-1/PD-L1, anticipating and preventing the resistance mechanism before it fully develops. By incorporating anti-PD-L2 therapy from the outset, the treatment regimen preemptively counteracts the upregulation of PD-L2 that occurs in dysbiotic patients, thereby maintaining therapeutic efficacy despite the presence of altered microbiota.
Data Source
AI summary
Provided herein are methods of treating cancer in an individual that has failed an anti-PD1/PD-L1 therapy, comprising selecting an individual that has failed a prior anti-PD1/PD-L1 therapy; and administering to the individual a first agent that blocks or disrupts PD-L2, RGMb, or a combination thereof, and a second agent that blocks or disrupts PD-L1, PD-1 or a combination thereof. Also provided herein are kits and therapeutic compositions for use in the methods described herein.