Customized CAR Polypeptides with DAP12 ITAMs
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Solution Overview
Problem
Current chimeric antigen receptor (CAR) T cell therapies for cancer treatment face challenges such as poor persistence and excessive T cell activation, leading to relapses and toxicities, despite improved efficacy with co-stimulatory domains, indicating a need for customized intracellular signaling to enhance immune effector cell function.
Innovation Solution
Development of CAR polypeptides with customized numbers of immunoreceptor tyrosine-based activation motifs (ITAMs) and costimulatory molecules, tailored for specific immune effector cells like αβ T cells, γδ T cells, and NK cells, using a DAP12 backbone with heterologous ITAMs and co-stimulatory domains to optimize signaling and reduce toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If co-stimulatory domains are added to CARs to improve efficacy, then tumor killing efficiency is improved, but biologic complications and toxicities increase
Solution Approach 1:
The patent changes the signaling parameters by using DAP12 backbone with customized ITAM motifs instead of traditional co-stimulatory domains. This parameter change in the intracellular signaling structure achieves effective T cell activation while reducing the biologic complications associated with conventional co-stimulatory domains like CD28 or 41BB.
Solution Approach 2:
The patent applies local quality by customizing the number and arrangement of ITAM motifs within the DAP12 backbone to create different signaling strengths tailored to specific immune effector cells. This localized optimization of signaling domains allows efficacy to be improved without uniformly increasing toxicity across all CAR T cell therapies.
2Productivity
If second-generation CARs with co-stimulatory domains are used to enhance efficacy, then complete remission rates improve, but CAR T cell persistence decreases
Solution Approach 1:
The patent changes the signaling duration and intensity parameters by using DAP12 with customized ITAM motifs, which provides sustained but controlled activation signals. This parameter optimization enables CAR T cells to maintain persistence while achieving high complete remission rates, resolving the trade-off between efficacy and durability.
3Productivity
If T cell activation is increased to improve tumor killing, then anti-tumor efficacy is improved, but excessive activation leads to severe toxicities
Solution Approach 1:
The patent implements feedback control through the DAP12-ITAM signaling system, which provides controlled and regulated activation signals. The customized ITAM motifs allow for fine-tuned signaling that activates T cells sufficiently for anti-tumor efficacy while preventing excessive activation that would lead to toxicities, effectively creating a self-regulating system.
Data Source
AI summary
Disclosed herein are chimeric antigen receptor (CAR) polypeptides that can be used with adoptive cell transfer having endodomains with a customized number of immunoreceptor tyrosine-based activation motifs (ITAMs). In some embodiments, the endodomain has a backbone of a receptor endodomain, such as CD8, CD3ζ, CD3δ, CD3γ, CD3ϵ, CD32 (Fc gamma RIIa), DAP10, DAP12, CD79a, CD79b, FcγRIγ, FcγRIIIγ, FcϵRIβ (FCERIB), and FcϵRIγ (FCERIG). In particular embodiments disclosed herein, the backbone is a DAP12 backbone. The disclosed endodomain is engineered to express at least one heterologous ITAM, including 1, 2, 3, 4, 5, or 6 ITAMs.