Antigen-Presenting Cell Reprogramming for Immune Tolerance
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Solution Overview
Problem
Current treatments for patients with haemophilia A who develop anti-drug antibodies, such as inhibitors against Factor VIII, are ineffective in 10-20% of cases, necessitating a new method to induce immune tolerance.
Innovation Solution
The method involves treating autologous antigen-presenting cells with an IDO-inducing agent like zebularine in the presence of Factor VIII or IX, skewing the cells towards a tolerogenic phenotype to establish immune tolerance by transferring these cells back to the patient, promoting regulatory T-cell differentiation and tolerance.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional immune tolerance induction (ITI) through regular FVIII infusions is used, then immune tolerance may be achieved in some patients, but treatment fails in 10-20% of patients
Solution Approach 1:
The patent segments the immune system's antigen presentation process by isolating and treating specific antigen-presenting cells (dendritic cells) ex vivo with IDO inducers before reinfusion, rather than attempting to modulate the entire immune system through systemic FVIII infusions. This targeted approach improves reliability by addressing the specific cellular mechanism responsible for inhibitor development.
Solution Approach 2:
The patent introduces IDO-inducing agents (such as zebularine, IFN-γ, or combinations thereof) as intermediary substances that mediate the transformation of dendritic cells into tolerogenic phenotypes. These intermediaries enable controlled immune tolerance induction by activating specific intracellular pathways (tryptophan degradation) that promote regulatory T cell differentiation, thereby overcoming the variability in response to traditional ITI.
2Reliability
If high doses of FVIII are administered continuously to induce tolerance, then immune tolerance may be achieved, but treatment complexity and cost increase
Solution Approach 1:
The patent applies preliminary action by pre-treating dendritic cells ex vivo with IDO inducers and drug antigen before reinfusion into the patient. This preparatory step programs the dendritic cells to induce tolerance upon reinfusion, eliminating the need for continuous high-dose FVIII administration and simplifying the overall treatment protocol to a series of discrete cellular therapy administrations.
Solution Approach 2:
The patent extracts the antigen-presenting cells (dendritic cells) from the patient's immune system, treats them externally with IDO inducers and drug antigen in controlled culture conditions, and then returns them to the patient. This extraction and external processing approach allows precise control over the tolerogenic differentiation process without requiring complex continuous infusion protocols.
3Reliability
If conventional ITI methods are used, then some patients achieve tolerance, but the treatment duration is prolonged and success is not guaranteed
Solution Approach 1:
The patent changes the fundamental parameter of immune tolerance induction from systemic drug exposure (FVIII infusions) to localized cellular reprogramming (IDO induction in dendritic cells). By altering the mechanism from pharmacological to immunological, the treatment achieves faster and more reliable tolerance induction, reducing treatment duration while improving success rates.
Solution Approach 2:
The patent employs a composite approach by combining multiple IDO-inducing agents (such as zebularine with IFN-γ, or other synergistic combinations) to treat dendritic cells. This composite strategy enhances the efficiency and speed of tolerogenic differentiation, enabling faster tolerance achievement compared to conventional single-modality ITI approaches.
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
This approach effectively reduces anti-drug antibody levels and induces immune tolerance, offering a customized and benign treatment with rapid tolerance achievement, particularly for patients non-responsive to traditional immune tolerance induction methods.
Implementation Method 1
Zebularine is a cytidine analogue containing a 2-(1H)-pyrimidinone ring which is an effective inhibitor of DNA methylation. Zebularine is known to induce IDO and the mechanism by which IDO is upregulated by zebularine has been suggested to be through epigenetic upregulation of the IDO1 gene.
Implementation Method 2
IDO1, indoleamine 2, 3-dioxygenase 1, is a haem-containing enzyme catalyzing the initial, rate-limiting step in tryptophan degradation that is known to have an important role in inducing immune tolerance both in experimental animals and in humans.
Data Source
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AI summary
There is provided according to the invention a method of treating a mammal suffering from or susceptible to an immune reaction to drug treatment comprising the raising of anti-drug antibodies which method comprises (a) ex-vivo treating antigen presenting cells obtained from the mammal with an agent which induces IDO in said antigen presenting cells in the presence of said drug or an epitope containing fragment thereof and (b) after IDO has been induced in said antigen presenting cells, transferring said cells back to the mammal thereby to establish immune tolerance to the drug.