Immune synapse-stabilizing chimeric antigen receptor (CAR) T cell
Inventors
Choi, Kyungho • Choi, Eun-Young • Nam, Giri • Park, Hyung-bae • Lee, Ji-Eun • Yeon, Hye-Ran
Assignees
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Publication Number
US-11965014-B2
Publication Date
2024-04-23
Expiration Date
Abstract
The present invention relates to a novel chimeric antigen receptor comprising a CD99 region which participates in immune synapse stabilization as a backbone of the chimeric antigen receptor, an immune cell comprising the same, and the uses thereof. CD99-based CAR-T cells are capable of forming very stable immune synapses with tumor cells compared to conventional backbone-based CAR-T cells and can exhibit improved tumor therapeutic efficiency, so they can be useful for immune cell therapy for the treatment of cancer.
Core Innovation
The document describes a chimeric antigen receptor (CAR) concept in which the backbone comprises an extracellular spacer domain and a transmembrane domain, and the transmembrane domain comprises a CD99 transmembrane domain. The CAR further comprises a CD99 intracellular juxtamembrane domain in the intracellular region, and optional inclusion of a CD99-derived extracellular spacer/hinge is described to stabilize CAR-T interactions with tumor cells.
The described problem is impaired immune synapse formation and impaired activation in CD99 knockout T-cell studies, including reduced TCR/LFA-1 clustering and diminished actin and microtubule network formation. The document further links disrupted actin–microtubule interaction to impaired immune function, and the described CAR design is presented as addressing this problem by using CD99-derived transmembrane and juxtamembrane elements to stabilize the immune synapse with tumor cells.
The document presents CAR designs defined by sequence features including CD99-derived extracellular and transmembrane/juxtamembrane components and intracellular signaling elements such as CD3 zeta and 4-1BB. Example variants include F58BBz, F45BBz, and F35BBz, compared against a conventional CD8 backbone CAR h19BBz, with immune synapse formation and tumor cell killing described in vitro and in vivo using Raji-Luc in NSG mice.
Claims Coverage
The independent claim covers a CAR with three structural regions—antigen-binding domain, backbone with extracellular spacer domain and transmembrane domain, and intracellular signaling domain—in which the transmembrane domain comprises a CD99 transmembrane domain and the CAR comprises a CD99 intracellular juxtamembrane domain, for at least 2 inventive structural features.
CD99 transmembrane in a CAR backbone
The transmembrane domain comprises a CD99 transmembrane domain in a CAR having an antigen-binding domain, a backbone with an extracellular spacer domain and the transmembrane domain, and an intracellular signaling domain.
CD99 intracellular juxtamembrane with intracellular signaling domain
The CAR comprises a CD99 intracellular juxtamembrane domain together with an intracellular signaling domain, where the CAR backbone includes an extracellular spacer domain and the transmembrane domain is CD99-derived.
Sequence-defined CD99 transmembrane domain
The CAR where the CD99 transmembrane domain includes an amino acid sequence designated as SEQ ID NO: 3.
Sequence-defined CD99 extracellular domain with contiguous residue range
The CAR where the CD99 extracellular domain is specified by SEQ ID NO: 5 or by a contiguous 20 to 70 amino-acid-residue sequence within SEQ ID NO: 5.
Sequence-defined CD99 intracellular juxtamembrane domain
The CAR in which the CD99 intracellular juxtamembrane domain includes an amino acid sequence represented by SEQ ID NO: 13.
Selectable intracellular signaling/co-stimulatory domain set
The CAR where the intracellular signaling domain includes selected intracellular signaling and/or co-stimulatory domains chosen from the specified set including CD3 elements and other listed signaling/co-stimulatory components, including 4-1BB (CD137), and including a ligand specifically binding to CD83.
Overall claim coverage centers on a CAR architecture that incorporates CD99-derived transmembrane and CD99 intracellular juxtamembrane elements, including sequence-specified CD99 extracellular, transmembrane, and juxtamembrane regions, combined with an intracellular signaling domain selected from defined signaling/co-stimulatory components.
Stated Advantages
Improved tumor elimination associated with shorter CD99 extracellular variants, as exemplified by F35BBz versus the conventional CD8 backbone CAR (h19BBz).
Improved immune synapse formation described in the context of CD99-derived CAR backbone variants and associated performance readouts.
Documented Applications
Treating cancer using an immune cell that expresses the disclosed CAR architecture including CD99 transmembrane domain and CD99 intracellular juxtamembrane domain.
In vitro and in vivo evaluation using Raji-Luc tumor control in NSG mice (described as a context for killing and immune synapse readouts).
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