Thymic stromal lymphopoietin receptor-specific chimeric antigen receptors and methods using same
Inventors
Assignees
US Department of Health and Human Services
Publication Number
US-11834509-B2
Publication Date
2023-12-05
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 also include additional domains such as a 4-1BB intracellular domain, a spacer, or both. These CARs can specifically bind to TSLPR, which is overexpressed on malignant cells particularly in certain forms of acute lymphoblastic leukemia (ALL). The invention also includes nucleic acids, recombinant expression vectors, host cells, populations of cells, antibodies or antigen binding portions thereof, and pharmaceutical compositions related to these CARs.
The problem being solved arises from the fact that cancer remains a public health concern with poor prognosis in many cases despite advances in chemotherapy and other treatments. There is an unmet need for additional treatments for cancers such as ALL, especially for those cases that relapse after standard treatment or become refractory. The existing CAR therapies targeting antigens such as CD19 have limitations, including patient relapse due to loss of CD19 expression. The invention addresses this gap by targeting TSLPR, a receptor overexpressed on approximately 5-10% of pediatric and adult ALL cases and associated with poor prognosis, offering a novel and potentially effective approach for cancer detection and treatment.
Claims Coverage
The patent claims include four independent methods centered on chimeric antigen receptors (CARs) specific for TSLPR, covering detection, determination of treatment candidacy, and treatment of TSLPR-overexpressing acute lymphoblastic leukemia (ALL). These claims focus on inventive features related to the CAR structure and its specificity.
Method of detecting TSLPR-overexpressing ALL using a specific CAR
A method involving contacting a sample containing ALL cells with a CAR comprising an antigen binding domain specific for TSLPR defined by specific light chain and heavy chain variable region CDR sequences, forming a complex, and detecting this complex as an indicator of TSLPR-overexpressing ALL.
Method of determining treatment candidacy based on TSLPR expression and specific CAR
A method to determine if a subject with ALL qualifies for treatment with a CAR comprising an antigen binding domain specific for TSLPR, by measuring TSLPR expression levels in ALL cells from the subject and comparing to controls, where the CAR contains specific light and heavy chain variable region CDR sequences.
Method of treating TSLPR-overexpressing ALL with T cells expressing a specific CAR
A method of treating TSLPR-overexpressing ALL in a mammal by administering an effective amount of T cells expressing a CAR with an antigen binding domain specific for TSLPR defined by particular light and heavy chain variable region CDR sequences.
Treatment of B cell precursor ALL and ALL associated with IKZF mutation using specific CAR T cells
Subsets of the treatment method claim specifying the CAR treatment for B cell precursor ALL and ALL associated with mutations in the IKZF gene, using CARs with antigen binding domains comprising defined CDR sequences.
The claims disclose methods involving CARs with antigen binding domains specific for TSLPR as defined by particular complementarity determining regions (CDRs) in the light and heavy chains, covering applications in detecting, determining treatment candidacy, and treating TSLPR-overexpressing ALL. Variants of CAR sequences encompassing SEQ ID NOs: 39-46, including short and long versions, are specifically claimed.
Stated Advantages
The CARs provide targeting and destruction of TSLPR-expressing cancer cells, reducing or eliminating cancer cells.
They facilitate the infiltration of immune cells into tumor sites and enhance or extend anti-cancer immune responses.
The short CAR variants demonstrate improved in vivo persistence and anti-leukemic activity compared to long CAR variants.
The therapies offer a potential effective treatment option for ALL cases refractory to conventional chemotherapy or those relapsing after CD19-targeted therapies.
TSLPR expression is restricted on normal tissues, potentially allowing specific targeting of cancer cells with limited off-target effects.
Documented Applications
Detecting the presence of a proliferative disorder, including TSLPR-overexpressing acute lymphoblastic leukemia (ALL), by contacting biological samples with TSLPR-specific CARs and detecting complexes.
Determining whether a subject with ALL is a candidate for CAR-based treatment by measuring TSLPR expression levels in patient samples.
Treating or preventing proliferative disorders, notably TSLPR-overexpressing cancers such as B cell precursor ALL and ALL associated with IKZF mutations, in mammals through administration of T cells expressing TSLPR-specific CARs.
Use of recombinant expression vectors, nucleic acids, host cells, and pharmaceutical compositions related to TSLPR-specific CARs in diagnostic and therapeutic methods.
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