Anti-CD22 chimeric antigen receptors
Inventors
Orentas, Rimas J. • Mackall, Crystal L. • Pastan, Ira H.
Assignees
US Department of Health and Human Services
Publication Number
US-9868774-B2
Publication Date
2018-01-16
Expiration Date
2032-10-19
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Abstract
The disclosure provides a chimeric antigen receptor (CAR) comprising a) an antigen binding domain of HA22, a transmembrane domain, and an intracellular T cell signaling domain; or b) an antigen binding domain of BL22, a transmembrane domain, and an intracellular T cell signaling domain comprising CD28 and/or CD137. 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 cancer in a mammal and methods of treating or preventing cancer in a mammal are also disclosed.
Core Innovation
The invention provides chimeric antigen receptors (CARs) comprising an antigen binding domain of HA22 or BL22 linked to transmembrane and intracellular T cell signaling domains. The CARs specifically bind to CD22, a lineage-restricted B cell antigen expressed on many B cell malignancies, including leukemias and lymphomas. The CAR constructs include second and third generation versions with intracellular signaling domains comprising CD28, CD137, and/or CD3 zeta.
The problem addressed by the invention is the poor prognosis and limited treatment options for cancers, particularly hematological malignancies such as non-Hodgkin's lymphoma and leukemia. Despite advances in chemotherapy, there is an unmet need for additional effective treatments targeting cancer cells.
By providing CARs specific to CD22, which is expressed on malignant B cells but not on early B cell stages or stem cells, the invention offers a means to target and destroy CD22-expressing cancer cells while avoiding damage to stem cells. The CARs incorporate antigen-binding domains derived from immunotoxins HA22 and BL22, known for their specificity to CD22, fused to T cell signaling components to redirect T cell specificity and function in a non-MHC-restricted manner. This approach enables T cells expressing the CARs to recognize and lyse cancer cells expressing CD22, potentially reducing tumor burden and improving treatment outcomes.
Claims Coverage
The patent includes a total of one independent claim directed to a chimeric antigen receptor and dependent claims related to nucleic acids, vectors, host cells, cell populations, pharmaceutical compositions, methods of detection, and cell expression of the CARs. The main inventive features encompass the CAR structures and their functional applications.
Chimeric antigen receptor comprising specific amino acid sequences
A chimeric antigen receptor comprising the amino acid sequence of any one of SEQ ID NO: 15-18 and 32, which includes antigen binding domains of HA22 or BL22 and intracellular signaling domains with CD28 and/or CD137.
Nucleic acid encoding the chimeric antigen receptor
Nucleic acids comprising nucleotide sequences encoding the CARs of SEQ ID NO: 15-18 and 32, including sequences selected from SEQ ID NOs: 22-23, 38, and further including signaling domain sequences of SEQ ID NOs: 24-25 and 39.
Recombinant expression vectors incorporating nucleic acids encoding the CARs
Vectors comprising the nucleic acids encoding the CARs, enabling expression of the CAR in host cells.
Host cells and populations of cells expressing the CARs
Isolated host cells, including human T cells, and populations thereof transformed or transduced with recombinant expression vectors encoding the CARs, capable of expressing the CAR on their surface.
Pharmaceutical compositions comprising the CARs
Pharmaceutical compositions comprising the CAR proteins and a pharmaceutically acceptable carrier suitable for administration.
Methods of detecting cancer using the CARs
Methods for detecting the presence of cancer in a mammal by contacting a sample with the CAR and detecting complexes formed with CD22-expressing cancer cells, specifically for B-cell leukemia or B-cell lymphoma expressing CD22.
The claims collectively cover CARs comprising specific amino acid sequences targeting CD22, nucleic acids encoding them, expression vectors and host cells expressing the CARs, pharmaceutical compositions, and methods for detecting CD22-expressing cancers using these CARs.
Stated Advantages
Targeting and destroying CD22-expressing cancer cells while avoiding early B cells and stem cells due to selective CD22 expression.
Providing an effective immunotherapeutic approach for hematological malignancies with poor prognosis and limited existing treatments.
Redirecting T-cell specificity in a non-MHC-restricted manner, potentially overcoming tumor evasion mechanisms.
Use of high affinity antigen binding domains (HA22) leading to more efficient tumor cell lysis.
Ability to reduce tumor burden and prolong survival in treated subjects (demonstrated in vivo).
Documented Applications
Treatment or prevention of cancers characterized by CD22 expression, including hematological malignancies such as B-cell leukemias and lymphomas.
Methods of detecting the presence of CD22-expressing cancer cells in mammalian subjects using CAR binding assays.
Use of the CAR-expressing host cells or pharmaceutical compositions as immunotherapies for cancer.
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