Hypoimmune O Rh-Negative Pluripotent Cells for Allogeneic Transplantation
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Solution Overview
Problem
Existing regenerative cell therapies face significant challenges due to immune rejection of allogeneic materials, limiting their efficacy and applicability, particularly in cases where autologous induced pluripotent stem cells (iPSCs) are technically and manufacturingly cumbersome, and allogeneic iPSC-based therapies risk rejection despite HLA-matching.
Innovation Solution
Development of hypoimmune pluripotent ABO blood type O Rhesus Factor negative (HIPO−) cells with reduced HLA-I and HLA-II expression, increased CD47 expression, and lack of ABO and Rh antigens, engineered to minimize immune rejection and facilitate universal compatibility.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If allogeneic iPSC-based therapies are used, then manufacturing is easier and cell products can be standardized, but immune rejection occurs
Solution Approach 1:
The patent applies parameter changes by modifying the immunogenic parameters of iPSCs through genetic engineering. Specifically, HLA class I and class II genes are knocked out to reduce antigen presentation, and CD47 is overexpressed to inhibit phagocytosis. These parameter modifications transform standard allogeneic iPSCs into hypoimmunogenic cells that can be manufactured standardizedly while avoiding immune rejection.
Solution Approach 2:
The patent creates a composite cell product by combining multiple genetic modifications within the same iPSC line. The cells contain both HLA knockout modifications and CD47 overexpression, forming a composite immunophenotype that simultaneously achieves reduced antigen presentation and enhanced resistance to phagocytosis, resolving the contradiction between manufacturability and immune compatibility.
2Reliability
If HLA-matched allogeneic cells are used, then immune compatibility is improved, but manufacturing complexity increases
Solution Approach 1:
The patent extracts the problematic HLA antigens from the cell surface by knocking out the genes responsible for HLA class I and class II expression. This extraction of immunogenic elements eliminates the need for HLA matching and typing procedures, thereby reducing manufacturing complexity while maintaining immune compatibility through alternative mechanisms (CD47-mediated protection).
3Reliability
If autologous iPSCs are used, then immune compatibility is maximized, but manufacturing time and complexity increase
Solution Approach 1:
The patent creates a universal cell product that can be used for multiple patients without requiring individual customization. By engineering iPSCs with hypoimmunogenic characteristics (HLA knockout and CD47 overexpression), a single standardized cell line can be transplanted into different recipients with reduced immune rejection risk, eliminating the time-consuming process of generating patient-specific autologous cells while maintaining immune compatibility.
Data Source
AI summary
The invention discloses for the first time pluripotent cells, including hypoimmune pluripotent ABO blood type O Rhesus Factor negative (HIPO−) cells, that evade rejection by the host allogeneic immune system and avoid blood antigen type rejection. The HIPO− cells comprise reduced HLA-I and HLA-II expression, increased CD47 expression, and a universal blood group O Rh− (“O−”) blood type. The universal blood type is achieved by eliminating ABO blood group A and B antigents as well as eliminating Rh factor expression, or by starting with an O− parent cell line. These new, novel HIPO− cells evade host immune rejection because they have an impaired antigen presentation capacity, protection from innate immune clearance, and lack blood group rejection. The cells of the invention also include O− pluripotent stem cells (iPSCO−) and O− embryonic stem cells (ESCO−). The invention further provides universally acceptable “off-the-shelf” pluripotent cells and derivatives thereof for generating or regenerating specific tissues and organs.