Fully Human CAR T Cells for CD123+ Malignancies
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Solution Overview
Problem
Current treatments for acute myeloid leukemia (AML) and other CD123+ malignancies face challenges such as high toxicity, limited efficacy, and rapid disappearance of CAR T cells after infusion, leading to inadequate long-term treatment prognosis and high risk of relapse.
Innovation Solution
Development of chimeric antigen receptors (CARs) with CD123 antigen binding domains that exhibit high surface expression on transduced T cells, promoting in vivo expansion and persistence, using entirely human antigen binding domains to avoid immune response and improve CAR T cell persistence and function.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If chemotherapy is used to treat AML, then tumor cells are killed, but high toxicity and limited efficacy occur
Solution Approach 1:
The patent uses CAR T cells as an intermediary biological agent to deliver targeted therapy. The CAR construct includes an antigen-binding domain that specifically recognizes CD123 on AML cells, a transmembrane domain for cell surface expression, and intracellular signaling domains for T cell activation. This intermediary system enables selective tumor cell killing while sparing normal cells, thereby improving efficacy and reducing toxicity compared to conventional chemotherapy.
Solution Approach 2:
The patent employs fully human antigen-binding domains in the CAR construct to change the immunogenicity parameter. By using human sequences instead of murine or chimeric sequences, the CAR T cells avoid immune rejection and persist longer in vivo, enhancing treatment durability and efficacy while reducing adverse immune responses.
2Reliability
If CAR T cells are infused to treat CD123+ malignancies, then anti-tumor activity is achieved, but rapid disappearance of CAR T cells occurs
Solution Approach 1:
The patent changes the antigen-binding domain sequence identity parameter from non-human to fully human. This parameter change eliminates immune recognition of the CAR T cells as foreign, preventing their clearance by the host immune system. As a result, CAR T cells persist longer in vivo, maintaining anti-tumor activity over extended periods and improving long-term treatment outcomes.
Solution Approach 2:
The patent converts the potential harm of immune rejection into a benefit by designing fully human CAR sequences that are invisible to the human immune system. This approach transforms what would normally be a harmful immune response into a favorable condition for sustained CAR T cell survival and function, thereby extending duration of action.
3Ease of manufacture
If murine-derived antigen binding domains are used in CAR design, then CAR T cells can be generated, but immunogenicity and allergic responses occur
Solution Approach 1:
The patent changes the species origin parameter of the antigen-binding domain from murine to fully human. This parameter change maintains the ability to generate functional CAR T cells while eliminating the immunogenicity associated with non-human sequences. The fully human sequences are recognized as self by the host immune system, preventing allergic and anaphylactic responses while preserving CAR T cell functionality.
Data Source
AI summary
Chimeric antigen receptors containing CD123 antigen binding domains are disclosed. Nucleic acids, recombinant expression vectors, host cells, antigen binding fragments, and pharmaceutical compositions, relating to the chimeric antigen receptors are also disclosed. Methods of treating or preventing cancer in a subject, and methods of making chimeric antigen receptor T cells are also disclosed.