CD83-Binding CAR Immune Cells for Selective GVHD Suppression
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Solution Overview
Problem
Allogeneic hematopoietic cell transplantation is limited by acute graft-versus-host disease (GVHD) due to donor T cells responding to host cells, and current immunosuppressive measures to control GVHD compromise post-transplant immunity.
Innovation Solution
Development of chimeric antigen receptor (CAR) polypeptides with an anti-CD83 binding agent, such as antibody fragments or aptamers, to suppress alloreactive donor T cells by targeting CD83-expressing cells, combined with genetically modified immune effector cells to express these CAR polypeptides.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If current immunosuppressive measures are used to control GVHD, then GVHD is suppressed, but post-transplant immunity is compromised
Solution Approach 1:
The patent introduces CAR-T cells as an intermediary therapeutic agent that specifically targets DCs expressing CD83. These engineered T cells act as a selective mediator that suppresses GVHD-inducing DCs while preserving other immune cells, thereby controlling GVHD without compromising overall post-transplant immunity.
Solution Approach 2:
The invention applies local quality by enabling selective suppression of specific DC subsets expressing CD83 through CAR-T cells, rather than applying broad immunosuppression. This localized targeting allows GVHD control while maintaining immunity in non-targeted immune cells and pathways.
2Object-affected harmful factors
If broad immunosuppression is applied to prevent GVHD, then GVHD is controlled, but overall immune function is reduced
Solution Approach 1:
CAR-T cells serve as a targeted intermediary that selectively eliminates GVHD-causing DCs without affecting other immune cells. This precise mediation allows GVHD control while preserving productive immune functions mediated by T cells, B cells, and other non-DC antigen-presenting cells.
Solution Approach 2:
The therapy applies local quality by directing suppression specifically at CD83-expressing DCs involved in alloreactivity, while leaving other immune cell populations and functions intact. This selective approach maintains overall immune productivity while controlling the harmful GVHD response.
3Reliability
If donor T cells are allowed to respond to host cells, then immune surveillance is maintained, but GVHD occurs
Solution Approach 1:
The patent introduces CAR-T cells as a protective intermediary that selectively eliminates host DCs presenting alloantigens to donor T cells. This intermediary action prevents the harmful T cell-DC interaction that causes GVHD while allowing donor T cells to maintain surveillance against tumors and infections through other antigen-presenting cell pathways.
Solution Approach 2:
The invention applies local quality by selectively blocking the specific DC-T cell interaction pathway that causes GVHD, while preserving other immune surveillance pathways. Donor T cells can still recognize and respond to tumor cells and pathogens through alternative antigen presentation mechanisms that do not involve CD83-expressing DCs.
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 CAR polypeptides effectively suppress GVHD while preserving post-transplant immunity by specifically targeting and modulating donor T cells, reducing the mortality associated with GVHD.
Implementation Method 1
The anti-CD83 binding agent is in some embodiments an antibody fragment that specifically binds CD83
Implementation Method 2
The anti-CD83 binding agent is in some embodiments an aptamer that specifically binds CD83
Data Source
AI summary
Disclosed are compositions and methods for preventing graft versus host disease (GVHD) in subjects receiving donor cells. In particular, chimeric antigen receptor (CAR) polypeptides are disclosed that can be used with adoptive cell transfer suppress alloreactive donor cells. Also disclosed are immune effector cells, such as T cells or Natural Killer (NK) cells, that are engineered to express these CARs. Therefore, also disclosed are methods of suppressing alloreactive donor cells in a subject receiving transplant donor cells that involves adoptive transfer of the disclosed immune effector cells engineered to express the disclosed CARs.