ALA Composition to Boost Checkpoint Inhibitor Antitumor Effect
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Solution Overview
Problem
There is a demand for pharmaceutical compositions that enhance the antitumor effect of immune checkpoint inhibitors such as anti-PD-1 and anti-PD-L1 antibodies, as existing therapies may be counteracted by the effects of 5-aminolevulinic acid (ALA) on PD-L1 expression and reactive oxygen species.
Innovation Solution
A pharmaceutical composition comprising 5-aminolevulinic acid (ALA) or its derivatives, administered alone or with metal-containing compounds like sodium ferrous citrate, enhances the antitumor effect of immune checkpoint inhibitors by improving mitochondrial function and inducing apoptosis in cancer cells, while mitigating immunosuppressive effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If ALA is administered to enhance mitochondrial function and induce apoptosis in cancer cells, then antitumor effect is improved, but immunosuppressive effects through PD-L1 upregulation and reactive oxygen species reduction counteract the therapy
Solution Approach 1:
The patent extracts and eliminates the harmful immunosuppressive components (bilirubin and carbon monoxide) generated by ALA metabolism through co-administration of HO-1 inhibitors. This allows retention of ALA's beneficial mitochondrial and apoptotic effects while removing its immunosuppressive side effects that counteract immune checkpoint inhibitor therapy.
Solution Approach 2:
The patent converts the harmful immunosuppressive effects of ALA into a beneficial situation by using HO-1 inhibitors to block the pathway that produces bilirubin and carbon monoxide. The ALA continues to exert its antitumor effects through mitochondrial dysfunction and apoptosis, while the immunosuppressive pathway is specifically inhibited, thereby converting a harmful side effect into a controlled therapeutic approach.
2Reliability
If ALA is used to improve mitochondrial activities and trigger caspase IX-type apoptosis, then cancer cell death is enhanced, but the upregulation of PD-L1 in dendritic cells suppresses T cell immunity
Solution Approach 1:
The patent introduces HO-1 inhibitors as intermediary substances that mediate between ALA's pro-apoptotic effects and its immunosuppressive effects. The HO-1 inhibitor specifically blocks the conversion of ALA-derived heme into bilirubin and carbon monoxide, thereby preventing PD-L1 upregulation in dendritic cells while allowing ALA to continue triggering caspase IX-type apoptosis in cancer cells.
3Reliability
If ALA and sodium ferrous citrate are administered to generate heme and enhance mitochondrial function, then antitumor activity is improved, but the resulting bilirubin and carbon monoxide reduce reactive oxygen species and suppress immunity
Solution Approach 1:
The patent converts the harmful reduction of reactive oxygen species into a beneficial situation by using HO-1 inhibitors to block the production of bilirubin and carbon monoxide. This allows the therapeutic generation of heme and subsequent mitochondrial dysfunction in cancer cells to proceed, while preventing the formation of antioxidants that would reduce tumor-killing reactive oxygen species and suppress immune responses.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The composition significantly enhances the antitumor effect of immune checkpoint inhibitors, leading to reduced tumor volume and potentially increased survival rates in cancer patients.
Implementation Method 1
an ALA or a derivative thereof is effective for cancer therapy by a presumed mechanism which enhances the heme or cytochrome in the mitochondria of a cancer cell
Implementation Method 2
improves mitochondrial activities such as the electron transport chain and the TCA cycle
Implementation Method 3
ALA together with an arbitrary sodium ferrous citrate (SFC) becomes a heme in the body, and this heme is degradated by an enzyme called a heme oxygenase 1 (HO-1) to change into bilirubin and carbon monoxide
Implementation Method 4
this bilirubin and carbon monoxide has a high antioxidant action and can directly/indirectly erase reactive oxygen species (ROS)
Implementation Method 5
in a dendritic cell which is the antigen-presenting cell, the above-described HO-1 (or bilirubin and carbon monoxide) changes (differentiates) the dendritic cell into a cell called a tolerogenic dendritic cell
Implementation Method 6
A tolerogenic cell is known to highly express PD-L1 and to perform specific immunological tolerance (immunosuppression) on the antigen presented on the T cell
Implementation Method 7
the antitumor effect by an anti-PD-1 antibody is related to the generation of reactive oxygen in T cells
Implementation Method 8
calls up the Bax and Bak systems to cause a caspase IX-type apoptosis when there is an abnormality in the nucleus that cannot be restored
Data Source
AI summary
The object of the invention is to provide a pharmaceutical composition for enhancing the antitumor effect by an immune checkpoint inhibitor. Provided is a pharmaceutical composition for enhancing the antitumor effect by an immune checkpoint inhibitor comprising 5-aminolevulinic acids (ALAs) as the active ingredient.