Compositions and methods for treating cancer with anti-CD19 immunotherapy
Inventors
Schneider, Dina • Orentas, Rimas J. • Dropulic , Boro • Dimitrov, Dimiter S. • Zhu, Zhongyu
Assignees
Lentigen Technology Inc • US Department of Health and Human Services
Publication Number
US-11708408-B2
Publication Date
2023-07-25
Expiration Date
2038-09-14
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Abstract
Chimeric antigen receptors containing human CD19 antigen binding domains are disclosed. Nucleic acids, recombinant expression vectors, host cells, antigen binding fragments, and pharmaceutical compositions, relating to the chimeric antigen receptors are also disclosed. Methods of treating or preventing cancer in a subject, and methods of making chimeric antigen receptor T cells are also disclosed.
Core Innovation
The invention provides novel chimeric antigen receptors (CARs) containing human CD19 antigen binding domains, along with nucleic acids, recombinant expression vectors, host cells expressing these receptors, antigen binding fragments, and pharmaceutical compositions related to the CARs. The CARs exhibit high surface expression on transduced T cells, a high degree of cytolysis of CD19-expressing cells, and transduced T cell expansion and persistence in vivo. Methods of treating or preventing cancer in subjects using these CARs and methods of making CAR T cells are also disclosed.
The problem addressed arises from the significant health burden of cancer, particularly B-cell malignancies that express CD19. Existing treatments such as chemotherapy, radiation, stem cell transplantation, antibody therapies including bi-specific antibodies like Blinatumomab, and murine-derived CAR-T therapies have limited efficacy and significant toxicity. Moreover, murine-derived CAR sequences are prone to induce immune rejection, reducing CAR T cell persistence and clinical efficacy. Although some CD19 CAR therapies have achieved FDA breakthrough designation with notable response rates, there remains a large patient population not adequately helped by these therapies. The challenge includes finding tumor-specific antigens and optimizing CAR design for improved T cell expansion and persistence.
The invention overcomes these shortcomings by providing fully human anti-CD19 antigen binding domains in CAR constructs which improve the functional activity and persistence of CAR-expressing T cells. The use of entirely human antigen binding domains reduces immunogenicity associated with murine sequences, potentially providing more durable and efficacious anti-tumor effects. The human CD19 CARs exhibit strong cytokine-induced cytolysis and cell surface expression, along with superior in vivo expansion compared to murine controls. The CAR constructs incorporate an extracellular CD19 binding domain connected through a linker to transmembrane and intracellular signaling domains including costimulatory and CD3-zeta domains, optimizing activation and persistence of the therapeutic T cells.
Claims Coverage
The independent claims cover isolated nucleic acid molecules encoding chimeric antigen receptors (CARs) comprising specific amino acid sequences, the CARs themselves, pharmaceutical compositions containing human T cells transduced with such CARs, vectors encoding these CARs, and host cells comprising these vectors.
Isolated nucleic acid encoding CAR with specified amino acid sequences
An isolated nucleic acid molecule encoding a chimeric antigen receptor comprising one of the amino acid sequences of SEQ ID NO: 20, 22, 24, 26, 28, 30, 32, or 34.
Chimeric antigen receptor encoded by the isolated nucleic acid
A CAR encoded by the isolated nucleic acid molecules encoding the amino acid sequences identified above.
Pharmaceutical composition comprising CAR-expressing human T cells
Compositions comprising populations of isolated human T cells transduced with nucleic acids encoding the disclosed CARs, isolated from humans having cancer.
Cancer types targeted by the pharmaceutical composition
The pharmaceutical compositions target hematological cancers such as leukemia (including chronic lymphocytic leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia) and lymphoma (including mantle cell lymphoma, non-Hodgkin's or Hodgkin's lymphoma), as well as multiple myeloma and a broad range of other cancers including various solid tumors of oral, digestive, respiratory, bones and joints, soft tissue, skin, central nervous system, breast, genital, urinary, eye, endocrine, and brain origins.
Vectors comprising nucleic acids encoding the CARs
Vectors that comprise the nucleic acids encoding the CARs, including DNA, RNA, plasmids, cosmids, herpes virus, measles virus, lentivirus, adenovirus, retrovirus, or combinations thereof.
Promoters in the vectors
Vectors comprising promoters that can be inducible, constitutive, tissue-specific, suicide promoters, or combinations thereof to control CAR expression.
Isolated host cells containing expression vectors
Isolated cells, particularly T cells including CD8+ T cells from humans, that contain vectors encoding the chimeric antigen receptors.
The claims broadly cover the isolated nucleic acids encoding specific CAR amino acid sequences, the CARs themselves, pharmaceutical compositions containing CAR-expressing T cells for treating cancers including hematological and solid tumors, vectors for expressing these CARs with various promoters, and host T cells (especially CD8+) comprising these vectors.
Stated Advantages
The fully human CD19 antigen binding domain decreases the risk of immune rejection and improves persistence and in vivo expansion of CAR-expressing T cells compared to murine-derived sequences.
The CARs exhibit high surface expression on transduced T cells and mediate potent, specific cytolytic activity against CD19-positive tumor cells.
Improved cytokine production by CAR T cells using human antigen binding domains enhances therapeutic activity beyond existing murine-based CARs.
The CAR design allows tuning of affinity for better balance of efficacy versus toxicity, potentially improving tumor specificity and reducing on-target off-tumor effects.
Documented Applications
Use of fully human anti-CD19 CARs and CAR T cells for treating or preventing cancers associated with CD19 expression, including hematological cancers such as chronic lymphocytic leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, mantle cell lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, multiple myeloma, and various solid tumors.
Methods of making CAR-containing T cells by transducing T cells with nucleic acid molecules encoding the disclosed anti-CD19 CARs.
Use of the disclosed CARs, antibodies, and antigen binding fragments for diagnosing diseases associated with CD19 expression by detecting CAR or antibody binding to cells or samples.
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