CAAR Cells Targeting ADAMTS13 Autoantibodies for TTP
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Solution Overview
Problem
Current treatments for thrombotic thrombocytopenia purpura (TTP) are nonspecific and often ineffective, leading to relapses and persistent organ damage due to the autoimmune response, as they do not completely eliminate the underlying pathogenic immune response.
Innovation Solution
Development of a chimeric autoantibody receptor (CAAR) comprising an extracellular domain with an ADAMTS13 autoantigen or fragment, a transmembrane domain, and an intracellular signaling domain, which is used to create genetically modified cells that specifically target and eliminate anti-ADAMTS13 specific B cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If therapeutic plasma exchange (TPE) is used to treat TTP, then mortality is reduced from approximately 90% to approximately 15%, but relapse rates remain high at 30-40% within 10 years and the treatment does not eliminate the underlying autoimmune response
Solution Approach 1:
The patent extracts and eliminates the specific pathogenic B cells that produce anti-ADAMTS13 autoantibodies using chimeric antigen receptor (CAR) T cell therapy. This targeted extraction approach removes the root cause of the autoimmune response rather than temporarily managing symptoms, thereby extending durable remission while maintaining the life-saving mortality benefits of TPE.
Solution Approach 2:
The patent introduces CAR T cells as an intermediary therapeutic agent that specifically targets and eliminates pathogenic B cells. These engineered T cells serve as a mediator between the immune system and the autoimmune pathology, providing sustained protection against relapse while preserving the immediate life-saving effects of plasma exchange.
2Duration of action of stationary object
If Rituximab is used as adjunct therapy to reduce relapse, then relapse rates are reduced, but relapse rates remain at 4-30% including multiple relapses
Solution Approach 1:
The patent replaces the non-specific immunosuppressive mechanism of Rituximab with a precision-engineered CAR T cell system that specifically targets anti-ADAMTS13 producing B cells. This substitution provides more reliable and complete elimination of pathogenic cells while avoiding the incomplete suppression and multiple relapses associated with Rituximab therapy.
Solution Approach 2:
The patent changes the therapeutic parameter from non-specific B cell depletion (Rituximab) to specific antigen-targeted B cell elimination (CAR T cells). This parameter change enables complete and durable remission by precisely eliminating only the pathogenic clone responsible for TTP while preserving other immune functions.
3Speed
If caplacizumab is used to interfere with vWF-platelet binding, then time to platelet recovery is reduced by 0.14 days and relapse risk is reduced by 67%, but it does not address the root autoimmune response
Solution Approach 1:
The patent applies preliminary action by using CAR T cells to eliminate the underlying autoimmune response before it can cause recurrent thrombotic events. This preemptive elimination of pathogenic B cells addresses the root cause while allowing caplacizumab to provide immediate symptomatic relief, creating a comprehensive two-pronged approach.
Solution Approach 2:
The patent converts the harmful autoimmune response into a benefit by using the specificity of the anti-ADAMTS13 autoantibody as a target for CAR T cell recognition. The very mechanism that causes disease (specific autoantibody production) becomes the basis for precise therapeutic targeting, allowing elimination of only the pathogenic cells while preserving healthy immune function.
Data Source
AI summary
The invention includes a chimeric autoantibody receptor (CAAR) comprising an extracellular domain comprising an ADAMTS13 autoantigen or fragment thereof, compositions comprising the CAAR, nucleic acids encoding the CAAR, vectors comprising a nucleic acid encoding the CAAR, and recombinant cells comprising the CAAR.