Stem Cell Engraftment Using CD117 Ablation and Immune Modulation
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Solution Overview
Problem
Current methods for hematopoietic stem cell transplantation, such as myeloablative conditioning with radiation and chemotherapy, are toxic and limit clinical utility due to adverse effects on patients, necessitating improved engraftment techniques.
Innovation Solution
A method involving a pre-transplantation conditioning regimen using an antibody specific for CD117 and agents that modulate immunoregulatory signaling, such as CD47 blockade and CD137 agonism, to selectively ablate endogenous stem cells without myeloablative treatment, allowing exogenous stem cells to engraft efficiently.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If myeloablative conditioning with radiation and chemotherapy is used to clear bone marrow niches, then stem cell engraftment is achieved, but patient toxicity and adverse effects increase
Solution Approach 1:
The patent divides the engraftment process into distinct phases: (1) selective ablation of endogenous stem cells using CD117-targeting agents, (2) modulation of immunoregulatory signaling through CD47 blockade and CD137 agonism, and (3) transplantation of exogenous stem cells. This segmentation allows each step to be optimized independently, achieving effective engraftment while minimizing toxicity by avoiding non-selective myeloablation.
Solution Approach 2:
The patent introduces immunoregulatory modulating agents as intermediaries between the ablation phase and engraftment phase. Specifically, CD47 blockade agents and CD137 agonists mediate the transition by modulating the immune microenvironment, preparing it to accept donor stem cells without requiring harsh myeloablative conditioning. These intermediaries bridge the gap between cell clearance and successful engraftment.
2Reliability
If traditional myeloablative regimens are used to prevent rejection and eradicate disease, then transplantation success is improved, but quality of life and patient safety deteriorate
Solution Approach 1:
The patent fundamentally changes the parameters of conditioning therapy by replacing high-dose cytotoxic agents with targeted immunomodulatory agents. Instead of using radiation and chemotherapy at maximally tolerated doses, the patent employs antibodies and immunomodulators that operate at lower doses with different mechanisms of action, thereby maintaining transplantation success while reducing adverse effects on patient quality of life.
Solution Approach 2:
The patent converts the harmful immune rejection response into a beneficial outcome by using CD137 agonism to enhance donor stem cell persistence and function. Rather than attempting to suppress the immune system with toxic immunosuppressants, the patent harnesses immune activation through CD137 signaling to promote graft acceptance and long-term engraftment, turning a potential harm into a therapeutic benefit.
3Object-affected harmful factors
If selective ablation of endogenous stem cells is performed without myeloablative treatment, then toxicity is reduced, but engraftment efficiency may be compromised
Solution Approach 1:
The patent performs preliminary actions to prepare the bone marrow niche before transplanting exogenous stem cells. By first selectively ablating endogenous stem cells and then modulating immunoregulatory signaling, the patent creates a pre-conditioned environment that is primed to accept donor cells. This preliminary preparation ensures that when exogenous stem cells are introduced, they encounter a favorable microenvironment that promotes efficient engraftment without requiring myeloablative treatment.
Solution Approach 2:
The patent replaces the mechanical/cytotoxic approach of myeloablative conditioning with a biological/immunomodulatory approach. Instead of using physical destruction through radiation or chemical destruction through chemotherapy, the patent employs antibody-mediated selective ablation and immune signaling modulation. This substitution of mechanism achieves the same functional outcome (clearance of endogenous cells and preparation of niche) with significantly reduced toxicity while maintaining engraftment efficiency.
Data Source
AI summary
The present invention provides a clinically applicable method of stem cell transplantation that facilitates engraftment and reconstitutes immunocompetence of the recipient without requiring radiotherapy or chemotherapy, and without development of GVHD or graft rejection. Aspects of the present invention are based on the discovery that the depletion of the endogenous stem cell niche facilitates efficient engraftment of stem cells into that niche. In particular, the present invention combines the use of selective ablation of endogenous stem cells with a combination of antibodies specific for CD117, and agents that modulate immunoregulatory signaling pathways, e.g. agonists of immune costimulatory molecules, in combination with the administration to the recipient of exogenous stem cells, resulting in efficient, long-term engraftment, even in immunocompetent recipients.