TAG72 targeted chimeric antigen receptor modified T cells for treatment of TAG72-positive tumors
Inventors
Priceman, Saul J. • Murad, John P. • Forman, Stephen J. • Shively, John (Jack) E. • YAZAKI, Paul • Colcher, David • Kozlowska, Anna • Lee, Hee Jun
Assignees
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Publication Number
US-12281152-B2
Publication Date
2025-04-22
Expiration Date
Abstract
Chimeric antigen receptors targeted to TAG72 and the use thereof to treat ovarian cancer and other cancers are described.
Core Innovation
The invention relates to a nucleic acid molecule and a population of human T cells expressing a chimeric antigen receptor (CAR) that targets Tag-72. The CAR comprises a scFv targeting Tag-72 comprising the amino acid sequence of SEQ ID NO: 33, together with a spacer, a CD4 or CD28 transmembrane domain, a CD28 or 4-1BB co-stimulatory domain, and a CD3ζ signaling domain.
The CAR architecture described in the document includes specified structural components for binding, orientation, and intracellular signaling, including spacer options and defined transmembrane and co-stimulatory domain selections. The spacer can include an IgG hinge region and can be defined by spacer length constraints and/or selected spacer amino acid sequences referenced by SEQ ID numbers.
The document further supports the claimed CAR design with described functional validation and in vivo performance. It reports Tag-72-dependent activation markers including CD137 and CD69, cytokine responses including IFNγ and IL-2, selective killing of Tag-72+ tumor cell lines and primary ascites-derived tumor cells, and improved in vivo efficacy with regional intraperitoneal delivery versus intravenous delivery in NSG xenograft models.
The disclosed application context includes solid tumors with Tag-72 expression, with particular reference to ovarian cancer models and primary ovarian ascites. The document also discusses antigen escape associated with Tag-72 loss in recurrences and describes aspects intended to support tracking/selection, including optional truncated EGFRt.
Claims Coverage
The partial content includes two independent claims: one directed to a nucleic acid molecule encoding a Tag-72 CAR with defined structural and signaling components, and one directed to a population of human T cells expressing the same CAR architecture. Across the dependent claims, the main inventive aspects are refined by specifying exact domain sequences and spacer configurations via SEQ ID references and by applying constraints such as spacer length ranges and hinge inclusion.
Tag-72 CAR nucleic acid encoding defined architecture
A nucleic acid molecule comprising a nucleotide sequence encoding a chimeric antigen receptor (CAR), wherein the CAR comprises a scFv targeting Tag-72 comprising the amino acid sequence of SEQ ID NO: 33, a spacer, a CD4 or a CD28 transmembrane domain, a CD28 or 4-1BB co-stimulatory domain, and a CD3ζ signaling domain.
Tag-72 CAR expressing human T-cell population
A population of human T cells expressing a CAR, wherein the CAR comprises a scFv targeting TAG-72 comprising the amino acid sequence of SEQ ID NO:33, a spacer, a CD4 or a CD28 transmembrane domain, a CD28 or 4-1BB co-stimulatory domain, and a CD3ζ signaling domain.
Claim coverage is centered on specifying a Tag-72-targeting CAR defined by a SEQ ID-specified Tag-72 scFv, a spacer region, selected CD4/CD28 transmembrane and CD28/4-1BB co-stimulatory domains, and a CD3ζ signaling domain. Dependent claims refine the scope by constraining spacer composition and length, including optional IgG hinge region, and by locking particular domain sequences using SEQ ID references.
Stated Advantages
Improved in vivo efficacy with regional intraperitoneal delivery versus intravenous delivery in NSG xenograft models.
Dose- and antigen-dependent T-cell activation, including activation markers CD137 and CD69 and cytokine responses IFNγ and IL-2.
Selective killing of Tag-72+ tumor cell lines and primary ascites-derived tumor cells.
Benefits of repeat dosing are reported in the document context.
CAR-based targeting addresses solid tumors with Tag-72 expression, including ovarian cancer models.
Documented Applications
Solid tumor treatment context targeting Tag-72, with particular reference to ovarian cancer models including NSG xenograft models and OVCAR3 and OV90.
Use with primary ovarian ascites-derived tumor cells for Tag-72-dependent activity.
In vivo delivery comparison for CAR T cells, reporting regional intraperitoneal delivery versus intravenous delivery in NSG xenograft models.
Discussion of antigen escape and heterogeneity linked to Tag-72 loss in recurrences.
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