Compositions and methods for treating cancer with anti-CD38 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-11103533-B2
Publication Date
2021-08-31
Expiration Date
2039-11-27
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Chimeric antigen receptors containing CD38 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 CD38 antigen binding domains, along with nucleic acids, recombinant expression vectors, host cells, antigen binding fragments, and pharmaceutical compositions related to the CARs. Methods for treating or preventing cancer in a subject and methods for making CAR T cells are also disclosed. These CARs exhibit high surface expression on transduced T cells, a high degree of cytolysis, and promote transduced T cell in vivo expansion and persistence.
The problem addressed by the invention is the difficulty in treating cancers such as multiple myeloma (MM) and chronic lymphocytic leukemia (CLL), both CD38-positive malignancies, which have suboptimal treatment efficacy and associated toxicities. Current first line therapies often cause broad immunosuppression and systemic toxicities. CAR-based approaches targeting CD38-positive malignancies offer therapeutic options with expected advantages over chemotherapy, including selective targeting of CD38-positive tumor cells and tumor stem cells, reduced toxicity, longer-term persistence, and better elimination of minimal residual disease, thereby reducing relapse probability.
The invention improves upon prior CAR designs by using unique human single-chain variable fragment (hScFv) sequences in the CAR design instead of murine-derived ScFvs. This humanization avoids risks of immunogenicity, allergic or anaphylactic responses, and CAR T cell elimination observed with mouse-derived sequences. The CARs' modular design includes an extracellular CD38-binding domain, transmembrane domains, and intracellular signaling motifs, with optimized linker and signaling domains, driving enhanced functional activity such as cytokine-induced cytolysis, T cell expansion, and persistence.
Claims Coverage
The patent claims focus on a method of treating hematological cancer using CAR-modified T cells comprising CARs with specific CD38 antigen binding domains, transmembrane domains, and intracellular signaling domains.
Method of treating hematological cancer with CAR T cells targeting CD38
Administering CAR-modified T cells to a human subject, where each CAR comprises an extracellular antigen binding domain with a CD38 antigen binding domain including specific amino acid sequences (SEQ ID NOs: 6, 8, 10, 22, 24), at least one linker/spacer domain, at least one transmembrane domain, and at least one intracellular signaling domain, under control of a promoter, with CAR amino acid sequences selected from SEQ ID NOs: 90, 92, 94, 104, 106, and where the CAR T cells are autologous to the subject.
Transmembrane domain composition
The at least one transmembrane domain of the CAR comprises a transmembrane domain from specific proteins including alpha, beta, or zeta chains of the T-cell receptor, CD8, CD28, CD3 epsilon, CD45, CD4, CD5, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, or CD154.
Linker or spacer domain linkage
The CD38 antigen binding domain and intracellular signaling domains are connected to the transmembrane domain by at least one linker or spacer domain, with the linker/spacer derived from the extracellular domain of CD8, TNFRSF19, or CD28.
Leader nucleotide peptide presence
The CD38 antigen binding domain is preceded by a leader nucleotide peptide sequence.
Intracellular signaling domain composition
The intracellular signaling domain comprises a CD3 zeta intracellular domain and may include costimulatory domains or primary signaling domains, with costimulatory domains selected from OX40, CD70, CD27, CD28, CD5, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), DAP10, DAP12, and 4-1BB (CD137).
Nucleic acid sequence composition
The nucleic acid sequence encoding the CD38 antigen binding domain comprises nucleotide sequences from SEQ ID NOs: 5, 7, 9, 21, or 23, or sequences with 85-99% identity thereto.
Cancer types treated
The methods cover treatment of multiple myeloma, leukemia including acute myeloid leukemia (AML), blastic plasmacytoid dendritic cell neoplasm (BPDCN), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), acute lymphoblastic T cell leukemia (T-ALL), acute lymphoblastic B cell leukemia (B-ALL), and lymphomas including mantle cell lymphoma, non-Hodgkin's lymphoma, and Hodgkin's lymphoma.
The claims protect methods of treating hematological cancers by administering human CAR T cells expressing fully human CD38 antigen binding domains with specific sequences, linked via defined linker and transmembrane domains, and containing intracellular signaling domains, directed to various hematological malignancies including multiple myeloma, leukemias, and lymphomas.
Stated Advantages
The CAR T cells provide specific and efficacious anti-tumor effects with high surface expression, cytolytic activity, and in vivo expansion and persistence.
The use of entirely human antigen binding domains avoids immunogenicity and allergic/anaphylactic reactions associated with mouse-derived ScFvs, improving CAR T cell persistence and function.
CAR T cells avoid the broad immunosuppression and systemic toxicities associated with conventional chemotherapy and immunotherapy combinations.
The CAR T cells have the potential to provide long-term therapeutic effects as a 'living drug', obviating the need for repeated treatments and reducing disease relapse.
CAR approaches may better eliminate minimal residual disease and tumor stem cells compared to chemotherapy, leading to improved long-term prognosis.
Certain CAR constructs can kill tumors efficiently with lower cytokine release, potentially reducing the risk of cytokine release syndrome and improving safety.
Documented Applications
Treatment or prevention of cancer in a subject, including hematological cancers such as multiple myeloma, chronic lymphocytic leukemia, acute myeloid leukemia, lymphoma, and other CD38-positive malignancies.
Use of CAR-modified T cells expressing CD38 antigen binding domains to treat refractory cancers non-responsive to chemotherapeutic agents.
Generation of persisting genetically engineered T cell populations in humans diagnosed with cancer for long-term therapeutic effects.
Methods of making CAR T cells by transducing T cells with nucleic acids encoding the disclosed CARs.
Diagnostic methods of detecting CD38 expression in cells or samples using human anti-CD38 antibodies or antigen binding fragments to diagnose and prognose CD38-related diseases.
Interested in licensing this patent?