CD33 DARIC and CAR Architecture for Controlled T Cell Signaling
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Solution Overview
Problem
Existing CAR T cell therapies for cancer treatment face limitations such as poor CAR expression, rapid cell disappearance, disappointing clinical activity, and antigen escape, necessitating improved CAR architectures and mechanisms for sensing and integrating chemical and biological information.
Innovation Solution
Development of VHH-based dimerizing agent regulated immunoreceptor complexes (DARICs) and chimeric antigen receptors (CARs) that bind CD33, including polypeptides with FRB and FKBP multimerization domains, bridging factors like AP21967, and costimulatory domains, to provide spatial and temporal control over immune effector cell signaling.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If scFv-based chimeric antigen receptors (CARs) are used for cancer treatment, then adoptive cell therapy can be delivered, but CAR expression is poor and cells disappear rapidly after infusion
Solution Approach 1:
The patent divides the CAR into separate functional components: a binding domain (scFv or VHH) that recognizes CD33, a transmembrane domain, and intracellular signaling domains (CD3ζ, CD137, CD28). This segmentation allows each component to be optimized independently for its specific function, improving overall CAR performance and cell persistence.
Solution Approach 2:
The patent creates a composite receptor structure combining multiple signaling domains (CD3ζ for primary signaling, CD137 for co-stimulation, CD28 for additional activation) within a single CAR construct. This composite approach provides synergistic signaling that enhances T cell activation, persistence, and anti-tumor activity.
2Reliability
If existing CAR architectures are used, then cancer treatment can be initiated, but clinical activity is disappointing and antigen escape occurs
Solution Approach 1:
The patent designs a universal CAR architecture that can recognize multiple CD33 splice variants (full-length CD33, C2 variant lacking exon 2, and variants with early stop signals in exon 7a). The scFv or VHH binding domain is engineered to accommodate these structural variations, providing broad antigen recognition across different cancer cell subpopulations and preventing antigen escape.
Solution Approach 2:
The patent employs chemically regulated dimerization parameters (using rapamycin or AP21967 as dimerizing agents) to control CAR activation. This allows dynamic adjustment of receptor dimerization and signaling intensity, optimizing clinical response while managing toxicity.
3Productivity
If CAR T cell therapy is administered, then cancer treatment can be provided, but toxicity increases and spatial/temporal control is limited
Solution Approach 1:
The patent introduces dynamic control mechanisms using chemically inducible dimerization (FRB-FKBP system) that allows temporal regulation of CAR activation. The system transitions from a static, always-active CAR to a dynamic receptor that can be activated only when needed, providing spatial and temporal control over immune effector cell signaling to reduce off-target toxicity.
Solution Approach 2:
The patent uses a dimerizing agent (rapamycin or AP21967) as an intermediary molecule that bridges the FRB and FKBP domains, inducing CAR dimerization and activation only in the presence of the drug. This intermediary control mechanism enables precise regulation of therapeutic activity and minimizes unwanted immune responses.
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 DARICs and CARs enhance therapeutic efficacy by targeting CD33-expressing cells with improved activation and reduced toxicity, overcoming tonic signaling and antigen-independent issues, and effectively treating cancers like AML.
Implementation Method 1
a first polypeptide comprising: an FRB multimerization domain polypeptide or variant thereof; a CD8a transmembrane domain or a CD4 transmembrane domain
Implementation Method 2
a second polypeptide comprising: an anti-CD33 VHH antibody that has an amino acid sequence set forth in any one of SEQ ID NOs: 2-21
Data Source
AI summary
The present disclosure provides improved CD33 targeting polypeptides and compositions for adoptive T cell therapies for treating, preventing, or ameliorating at least one symptom of a cancer, infectious disease, autoimmune disease, inflammatory disease, and immunodeficiency, or condition associated therewith.