CD123 specific chimeric antigen receptors for cancer immunotherapy
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Publication Number
US-11919961-B2
Publication Date
2024-03-05
Expiration Date
Abstract
The present invention relates to Chimeric Antigen Receptors (CAR) that are recombinant chimeric proteins able to redirect immune cell specificity and reactivity toward selected membrane antigens, and more particularly in which extracellular ligand binding is a scFV derived from a CD123 monoclonal antibody, conferring specific immunity against CD123 positive cells. The engineered immune cells endowed with such CARs are particularly suited for treating lymphomas and leukemia.
Core Innovation
The invention provides an ex vivo method of engineering an allogeneic T cell for immunotherapy of a pre-malignant or malignant cancer condition characterized by CD123-expressing cells. The method includes providing a T cell, inactivating at least one gene encoding one or more components of a T-cell receptor (TCR) in the T cell, and introducing into the T cell at least one polynucleotide encoding a CD123 specific chimeric antigen receptor (CAR) to be expressed at the surface of the cell.
The CD123 specific CAR comprises an extracellular ligand binding domain including a heavy chain variable region and a light chain variable region from a monoclonal anti-CD123 antibody, wherein the heavy chain variable region comprises CDR sequences set forth in SEQ ID NOs: 67, 68, and 69, and the light chain variable region comprises CDR sequences set forth in SEQ ID NOs: 70, 71, and 72. The CAR further comprises an FcγRIIIα, CD8a, or IgG1 hinge, a CD8α transmembrane domain, and a cytoplasmic domain comprising a CD3-ζ signaling domain and a co-stimulatory domain from 4-1BB.
The described work includes CAR activity and cytotoxic function against CD123-high/low/negative targets, including degranulation (CD107a), IFN-γ release, and specific lysis. It also includes lead CAR selection based on reduced background activity and an in vivo AML xenograft demonstrating anti-CD123 activity via bioluminescence.
Claims Coverage
One independent claim is provided. It centers on ex vivo engineering of an allogeneic T cell for CD123-expressing pre-malignant or malignant cancer by TCR gene inactivation and introduction of a CD123-specific CAR with defined antibody-derived CDR sequences and specified hinge, transmembrane, and cytoplasmic signaling/co-stimulatory components.
Allogeneic ex vivo T cell engineering for CD123-expressing cancer
An ex vivo method of engineering a T cell suitable for an allogeneic immunotherapy treatment of a pre-malignant or malignant cancer condition characterized by CD123-expressing cells, comprising providing a T cell, inactivating at least one gene encoding one or more components of a T-cell receptor (TCR) in the T cell, and introducing into the T cell at least one polynucleotide encoding a CD123 specific chimeric antigen receptor (CAR) to be expressed at the surface of the cell.
CD123 CAR extracellular ligand binding domain defined by VH and VL CDR sequences
The CD123 specific CAR comprises an extracellular ligand binding domain comprising a heavy chain variable region and a light chain variable region from a monoclonal anti-CD123 antibody, wherein the heavy chain variable region comprises CDR sequences set forth in SEQ ID NOs: 67, 68, and 69, and wherein the light chain variable region comprises CDR sequences set forth in SEQ ID NOs: 70, 71, and 72.
CD123 CAR hinge, transmembrane, and cytoplasmic signaling with CD3-ζ and 4-1BB
The CD123 specific CAR comprises an FcγRIIIα, CD8a, or IgG1 hinge, a CD8α transmembrane domain, and a cytoplasmic domain comprising a CD3-ζ signaling domain and a co-stimulatory domain from 4-1BB.
Claim coverage is anchored in engineering an allogeneic T cell by inactivating TCR component gene(s) and introducing a CD123-specific CAR defined by anti-CD123 VH/VL CDR sequence sets and a cytoplasmic CD3-ζ signaling domain with 4-1BB co-stimulation.
Stated Advantages
CAR activity and cytotoxic function against CD123-high/low/negative targets, including degranulation (CD107a), IFN-γ release, and specific lysis.
Lead CAR selection based on reduced background activity.
In vivo AML xenograft demonstrating anti-CD123 activity via bioluminescence.
Documented Applications
Ex vivo immunotherapy of a pre-malignant or malignant cancer condition characterized by CD123-expressing cells.
Allogeneic immunotherapy treatment.
In vivo AML xenograft.
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