Universal anti-CD22 chimeric antigen receptor engineered immune cells
Inventors
Smith, Julianne • Duchateau, Philippe • DERRIEN, Murielle
Assignees
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Publication Number
US-11944643-B2
Publication Date
2024-04-02
Expiration Date
Abstract
The present invention relates to an engineered immune cell endowed with CD22 Chimeric Antigen Receptors (CD22 CAR) with a deletion in the TRAC gene that is able to redirect immune cell specificity and reactivity toward selected tumor cells. The engineered immune cells endowed with such CARs are particularly suited for treating relapsed refractory CD22 expressing cancers.
Core Innovation
The invention relates to an engineered human Universal Chimeric Antigen Receptor T Cell specific for CD22 (UCART22). The UCART22 includes an anti-CD22 chimeric antigen receptor and a safety switch. The anti-CD22 CAR comprises an extracellular domain including a hinge domain from CD8alpha and an antigen binding domain specific for CD22, a transmembrane domain from CD8alpha, and an intracellular signaling domain. The anti-CD22 CAR comprises a polypeptide sequence having at least 80% sequence identity with a full-length sequence of SEQ ID NO: 15.
The safety switch includes an RQR8 region linked to the anti-CD22 CAR by a cleavable peptide 2A linker, wherein the RQR8 region comprises the sequence of SEQ ID NO: 60. The disclosed UCART22 construct also includes rituximab mAb-specific epitopes configured between or linked relative to the antigen binding domain and the hinge domain, and optionally includes a QBEND-10 mAb-specific epitope.
In some embodiments, the UCART22 includes an inactivated TRAC gene with an insertion, deletion, or mutation in SEQ ID NO: 18, and exhibits undetectable T cell receptor activity or expression as measured by flow cytometry. Additional embodiments include at least one inactivated gene selected from dCK, β2 microglobulin (B2M), and CD52, or at least one additional inactivated gene selected from AHR, TGFβ receptor, IL-10 R, PD-1, or combinations thereof.
Claims Coverage
The provided material presents one independent claim directed to an engineered UCART22 CD22 CAR T cell with a defined anti-CD22 CAR architecture and a safety switch. The inventive coverage centers on four main features.
Anti-CD22 CAR with CD8alpha hinge and transmembrane domains
The anti-CD22 CAR comprises an extracellular domain with a hinge domain from CD8alpha and an antigen binding domain specific for CD22, a transmembrane domain from CD8alpha, and an intracellular signaling domain.
Anti-CD22 CAR sequence identity to SEQ ID NO: 15
The anti-CD22 CAR comprises a polypeptide sequence having at least 80% sequence identity with a full-length sequence of SEQ ID NO: 15.
Safety switch with RQR8 and cleavable 2A linker
The safety switch comprises an RQR8 region linked to the anti-CD22 CAR by a cleavable peptide 2A linker, wherein the RQR8 region comprises the sequence of SEQ ID NO: 60.
Rituximab epitope arrangement in the safety switch
The safety switch comprises rituximab mAb-specific epitopes configured between or linked relative to the antigen binding domain and the hinge domain, and optionally includes a QBEND-10 mAb-specific epitope.
The claim coverage centers on an engineered UCART22 CD22 CAR T cell with a CD8alpha-based CAR architecture, an anti-CD22 CAR polypeptide constrained by at least 80% identity to SEQ ID NO: 15, and a safety switch using an RQR8 region linked by a cleavable 2A linker with rituximab mAb-specific epitope arrangements, optionally including a QBEND-10 mAb-specific epitope.
Stated Advantages
Reduced cytokine release.
Limited GvHD.
Controlled in vivo activity.
Resistance to alemtuzumab (CAMPATH).
Resistance to purine nucleotide analogs (clofarabine/fludarabine).
Optional hypoxia resistance (HIF-1α).
Documented Applications
Treating relapsed/refractory CD22+ hematological cancers.
Combinations involving CD19/CD22.
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