Universal chimeric antigen receptor T cells specific for CD22
Inventors
Schiffer-Mannioui, Cecile • Duchateau, Philippe • GAUTRON, Anne-Sophie
Assignees
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Publication Number
US-11690873-B2
Publication Date
2023-07-04
Expiration Date
Abstract
The present invention relates to new CD22 Chimeric Antigen Receptors (CD22 CAR), an engineered immune cell endowed with said new CD22 CAR and comprising at least inactivated TRAC gene for use in therapy. The engineered immune cells endowed with such CARs are particularly suited for treating relapsed refractory CD22 expressing cancers.
Core Innovation
The document defines a CD22-specific chimeric antigen receptor (CAR) platform with at least one extracellular domain comprising an antigen binding domain specific for CD22, a hinge domain selected from an FcRIIIα, a CD8α, an IgG1, an IgG4, or a PD1 hinge, a transmembrane domain, and an intracellular signaling domain comprising a CD3ζ signaling domain having at least 95% identity with SEQ ID NO: 9. The antigen binding domain comprises a single chain variable fragment (scFv) specific for CD22, with VH/VL sequence combinations restricted to listed pairs of SEQ ID NOs.
The CAR further includes at least one monoclonal antibody (mAb)-specific epitope selected from specified amino acid sequences including CPYSNPSLC (SEQ ID NO: 91) and ELPTQGTFSNVSTNVSPAKPTTTA (SEQ ID NO: 92). The disclosed system is directed to universal off-the-shelf CD22 CAR T cells exemplified by UCART22, engineered with at least TRAC gene inactivation, and may include additional gene alterations such as CD52, dCK, HIF-1alpha, B2M, AHR, TGFβ receptor, IL-10R, and PD-1.
The document also describes CD22 CAR delivery and transduction concepts including integrative lentiviral vectors and non-integrative lentiviral vectors, as well as engineering at the TRAC locus using TALEN and rAAV6 repair matrix concepts. It further provides in vivo assessment, a phase I clinical trial rationale/design for allogeneic CD22 CAR T cells with UCART22 dosing and dose-escalation framework, and therapeutic use for relapse/refractory CD22-expressing hematologic cancers, including B-ALL.
Claims Coverage
The consolidated claim coverage identifies one CD22-specific CAR architecture with constrained scFv VH/VL combinations, a selected hinge, a transmembrane domain, and a CD3ζ intracellular signaling domain with at least 95% identity to SEQ ID NO: 9. Additional inventive features present across the claims include mAb-specific epitope selection, TRAC gene inactivation, additional gene alterations, and administration sequencing for CAR T products.
Cd22-specific car architecture with scFv and hinge selection
At least one extracellular domain comprising an antigen binding domain specific for CD22, wherein the antigen binding domain comprises a single chain variable fragment (scFv) specific for CD22, with VH/VL sequence combinations restricted to listed pairs of SEQ ID NOs, and a hinge domain comprising an FcRIIIα, a CD8α, an IgG1, an IgG4, or a PD1 hinge.
Transmembrane domain
A transmembrane domain.
Intracellular cd3zeta signaling domain with identity threshold
An intracellular signaling domain comprising a CD3ζ signaling domain comprising an amino acid sequence having at least 95% identity with SEQ ID NO: 9.
MAb-specific epitope selection
At least one monoclonal antibody (mAb)-specific epitope selected from CPYSNPSLC (SEQ ID NO: 91) and ELPTQGTFSNVSTNVSPAKPTTTA (SEQ ID NO: 92), together with additional specified epitope sequences in the claims.
TRAC gene inactivation in an engineered immune cell
An immune cell that includes inactivation of a TRAC (T Cell Receptor Alpha Constant) gene.
Additional gene alterations in the engineered immune cell
An immune cell that further includes at least one additional gene alteration selected from CD52, dCK, HIF-1alpha, B2M, AHR, a TGF receptor, an IL-10 receptor, PD-1, or combinations thereof.
Sequential or combined administration scheme for two car t products
A method of administering UCART19 and UCART22 in a specified sequence, with one CAR T product given first and then the other given alone or in combination for one or more administrations.
The consolidated claims are centered on a CD22 CAR defined by a CD22-specific scFv with restricted VH/VL pairings, hinge selection from FcRIIIα/CD8α/IgG1/IgG4/PD1, a transmembrane domain, and a CD3ζ domain meeting an identity requirement, together with specified mAb-specific epitopes. Dependent refinements cover TRAC gene inactivation, additional gene alterations, and administration schemes involving UCART19 and UCART22.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Therapeutic use for relapse/refractory CD22-expressing hematologic cancers, including B-ALL.
CAR T cell depletion using epitope-specific mAbs.
Possible control of CAR activity via mAb targeting/depletion.
Phase I clinical trial rationale/design for allogeneic CD22 CAR T cells with UCART22 dosing and a dose-escalation framework, including lymphodepletion chemotherapy and DLT/MTD considerations.
In vivo assessment in an anti-cancer mouse xenograft model with bioluminescent signals and complete clearance claims.
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