Compositions and methods for treating cancer with anti-CD123 immunotherapy
Inventors
Orentas, Rimas J. • Schneider, Dina • Dropulic , Boro • Dimitrov, Dimiter S. • Zhu, Zhongyu
Assignees
Lentigen Technology Inc • US Department of Health and Human Services
Publication Number
US-10844128-B2
Publication Date
2020-11-24
Expiration Date
2039-09-20
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Abstract
Chimeric antigen receptors containing CD123 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 chimeric antigen receptors (CARs) containing CD123 antigen binding domains, nucleic acids, recombinant expression vectors, host cells expressing the receptors, antigen binding fragments, and pharmaceutical compositions related to these CARs. The CARs exhibit a high surface expression on transduced T cells, demonstrate a high degree of cytolysis, and promote in vivo expansion and persistence of the transduced T cells. The methods disclosed include treating or preventing cancer in a subject and making CAR T cells.
The problem addressed is the urgent need for improved therapeutic modalities for CD123+ malignancies, such as acute myeloid leukemia (AML) which has low survival rates and limited effective treatment options. Existing first line therapies have high toxicity and often fail to achieve sufficient tumor remission, leading to relapse. Prior CAR approaches used murine-derived antigen binding domains that carry risks of immunogenicity and life-threatening immune responses. Therefore, there is a long-felt need for novel CAR designs with specific and efficacious anti-tumor effects without these shortcomings.
Claims Coverage
The patent includes one independent claim directed to a method of treating B-cell cancer or lymphoma using autologous T cells expressing a CAR with specific structural domains.
Method of treating B-cell cancer or lymphoma with autologous CAR T cells
Administering to a subject a pharmaceutical composition comprising an anti-tumor effective amount of autologous T cells expressing a chimeric antigen receptor (CAR) comprising at least one extracellular CD123 antigen binding domain with specific amino acid sequences, at least one linker or spacer domain, at least one transmembrane domain, and at least one intracellular signaling domain to treat the cancer.
Inclusion of specific transmembrane domains in the CAR
The CAR comprises at least one transmembrane domain selected from the alpha, beta, or zeta chain of the T-cell receptor, CD8, CD28, CD3 epsilon, CD45, CD4, CD5, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, or CD154.
Linkage of antigen binding domain and intracellular signaling domain via linker or spacer
The CD123 extracellular antigen binding domain and/or the intracellular signaling domain are connected to the transmembrane domain via at least one linker or spacer domain.
Specific source of linker or spacer domain
The linker or spacer domain is derived from the extracellular domain of CD8, TNFRSF19, or CD28 and is linked to the transmembrane domain.
Preceding leader peptide sequence
The CD123 antigen binding domain is preceded by a leader nucleotide sequence encoding a leader peptide.
Inclusion of CD3 zeta intracellular domain
The intracellular signaling domain of the CAR further includes a CD3 zeta intracellular domain.
Presence of costimulatory and primary signaling domains
The intracellular signaling domain comprises a costimulatory domain, a primary signaling domain, or a combination thereof.
Examples of costimulatory domains
The costimulatory domain includes functional signaling domains of OX40, CD70, CD27, CD28, CD5, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), DAP10, DAP12, or 4-1BB (CD137).
Targeted cancers
The method addresses treatment of hematological B-cell cancers, specifically chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), acute lymphoblastic B cell leukemia (B-ALL), and lymphomas including mantle cell lymphoma, non-Hodgkin's lymphoma, and Hodgkin's lymphoma.
The claims recite a method of treating B-cell cancers and lymphomas using autologous T cells expressing a CAR comprising specific CD123 antigen binding domains, linker or spacer domains, transmembrane domains, and intracellular signaling domains with defined structural and functional features, targeting a range of hematological malignancies.
Stated Advantages
CAR approaches targeting CD123 may achieve better efficacy in eliminating CD123+ tumor cells and tumor stem cells compared to chemotherapy.
CAR T cells avoid toxicities associated with chemotherapy.
CAR T cells are expected to more efficiently eliminate minimal residual disease, resulting in better long-term treatment prognosis.
CAR123 can be used for tumor debulking as a bridge to transplant, helping patients with high tumor burden become eligible for bone marrow transplant.
Use of unique human ScFv sequences in CAR design reduces immunogenicity risks associated with murine-derived sequences, avoiding allergic or anaphylactic responses and CAR T elimination.
The disclosed CARs exhibit high surface expression, potent target-specific cytolysis, and promote in vivo transduced T cell expansion and persistence.
Certain CAR constructs show strong cytokine secretion in response to tumor cells while potentially minimizing cytokine release syndrome, offering better safety profiles.
Documented Applications
Treatment of cancers associated with dysregulated CD123 expression, including hematological cancers such as acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), mantle cell lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, multiple myeloma, and other CD123+ malignancies.
Use of CAR T cells expressing the disclosed CARs for tumor debulking as a bridge to bone marrow transplant.
Methods for diagnosing diseases, disorders or conditions associated with the expression of CD123.
Inhibition of CD123-dependent T cell inhibition and alteration of tumor microenvironment to inhibit tumor growth.
Induction of anti-tumor immunity by administration of T cells transduced with the disclosed CARs.
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