Thymic stromal lymphopoietin receptor-specific chimeric antigen receptors and methods using same
Inventors
Assignees
US Department of Health and Human Services
Publication Number
US-10676528-B2
Publication Date
2020-06-09
Expiration Date
2034-10-30
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Abstract
The invention provides a chimeric antigen receptor (CAR) comprising an antigen binding domain specific for TSLPR, a transmembrane domain, and an intracellular T cell signaling domain. Nucleic acids, recombinant expression vectors, host cells, populations of cells, antibodies, or antigen binding portions thereof, and pharmaceutical compositions relating to the CARs are disclosed. Methods of detecting the presence of a proliferative disorder, e.g., cancer, in a mammal and methods of treating or preventing a proliferative disorder, e.g., cancer, in a mammal are also disclosed.
Core Innovation
The invention provides chimeric antigen receptors (CARs) comprising an antigen binding domain specific for thymic stromal lymphopoietin receptor (TSLPR), a transmembrane domain, and an intracellular T cell signaling domain. The CAR may further comprise a 4-1BB intracellular domain, a spacer, or both. The invention also provides related nucleic acids, recombinant expression vectors, host cells, cell populations, antibodies or antigen binding portions thereof, and pharmaceutical compositions relating to these CARs.
The problem being solved is the unmet need for additional treatments of cancer, particularly acute lymphoblastic leukemia (ALL), which despite advances in chemotherapy, continues to have a poor prognosis especially in high-risk, relapsed, or refractory cases. Current CAR therapies targeting CD19 show potent activity but some patients do not respond, and relapses due to loss of CD19 expression have been observed, underscoring the need for new targets and treatments.
Claims Coverage
There are multiple inventive features disclosed across the independent claims related to a chimeric antigen receptor (CAR) specific for TSLPR, its structure, components, and pharmaceutical compositions.
Antigen binding domain specificity for TSLPR
A CAR comprising an antigen binding domain specific for TSLPR, wherein the antigen binding domain includes defined complementarity determining region (CDR) sequences from specific light and heavy chain variable regions as identified by SEQ ID NOS.
Structure of antigen binding domain
The antigen binding domain comprises a light chain variable region and a heavy chain variable region, each with corresponding CDR sequences and framework sequences as specified.
Presence of linker in antigen binding domain
The antigen binding domain includes a linker sequence, specifically as defined by SEQ ID NO: 17, connecting the heavy and light chain variable regions.
Transmembrane domain includes CD8 sequences
The CAR transmembrane domain comprises CD8 amino acid sequences including the CD8α hinge and transmembrane domain, specifically SEQ ID NOS: 35 and 36.
Intracellular T cell signaling domains include 4-1BB or CD3 zeta
The intracellular T cell signaling domain comprises the 4-1BB amino acid sequence (SEQ ID NO: 37), the CD3 zeta amino acid sequence (SEQ ID NO: 38), or both.
Specific CAR amino acid sequences
The CAR comprises specific amino acid sequences as provided in any one of SEQ ID NOs: 39-46, incorporating the aforementioned domains and regions.
Pharmaceutical composition including the CAR
A pharmaceutical composition comprising the CAR as described and a pharmaceutically acceptable carrier.
The independent claims cover CARs specific for TSLPR with defined antigen binding domains comprising particular light and heavy chain variable regions and CDRs, inclusion of linkers, CD8-derived transmembrane domains, 4-1BB and/or CD3 zeta intracellular signaling domains, specific amino acid sequences for the CARs, and pharmaceutical compositions containing such CARs.
Stated Advantages
Permit targeting and destruction of TSLPR-expressing cancer cells, particularly acute lymphoblastic leukemia cells.
Enhance immune cell infiltration to tumor sites and extend anti-cancer responses.
Demonstrate selective activity against cancer cells with higher TSLPR expression, sparing normal cells with limited TSLPR expression.
The short CAR construct shows improved in vivo anti-leukemic activity associated with increased persistence of CAR T cells.
Documented Applications
Treatment or prevention of proliferative disorders, including cancer such as B-cell precursor acute lymphoblastic leukemia that overexpresses TSLPR.
Detection of cancer presence in mammals by using the CARs or related molecules to detect TSLPR-expressing cells.
Determining patient candidacy for TSLPR CAR therapy by measuring TSLPR expression levels in biological samples.
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