Anti-SLAMF7 chimeric antigen receptors
Inventors
KOCHENDERFER, James N. • Feldman, Steven A.
Assignees
US Department of Health and Human Services
Publication Number
US-11951131-B2
Publication Date
2024-04-09
Expiration Date
2039-06-26
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Abstract
Provided are chimeric antigen receptors (CARs) having antigenic specificity for B-cell Maturation Antigen (SLAMF7). Also provided are related nucleic acids, recombinant expression vectors, host cells, populations of cells, and pharmaceutical compositions relating to the CARs. Methods of treating or preventing cancer in a mammal are also provided.
Core Innovation
This invention provides chimeric antigen receptors (CARs) having antigenic specificity for signaling lymphocyte activating molecule F7 (SLAMF7), also known as B-cell Maturation Antigen. The CARs comprise an antigen recognition domain, a transmembrane domain, and a T cell activation domain, specifically designed to target SLAMF7, which is highly expressed on malignant plasma cells in multiple myeloma (MM). The invention also includes nucleic acids encoding these CARs, recombinant expression vectors, host cells expressing the CARs, and pharmaceutical compositions containing such CAR materials.
The problem being addressed arises from the limitations of current cancer therapies, including chemotherapy, which often results in remission but followed by relapse and death in cancers such as multiple myeloma. Existing CAR T-cell therapies targeting B-cell maturation antigen (BCMA) face challenges including variable expression of BCMA on MM cells and loss of BCMA expression post-treatment, limiting their efficacy. Additionally, while SLAMF7 is a promising target due to its high expression on MM cells and limited expression on non-hematologic tissues, it is also expressed on some normal leukocytes, raising concerns about toxicity and off-target effects. Hence, there is a need for CAR constructs targeting SLAMF7 with safety mechanisms to mitigate depletion of normal leukocytes and associated toxicities.
The invention further provides CARs combined with regulatory elements, such as suicide genes (e.g., inducible caspase 9 (IC9)) that can modulate the activity of CAR-expressing cells by acting as on/off switches. This allows on-demand reduction or elimination of CAR-expressing cells to manage potential toxicities such as chronic cytopenias or cytokine release syndrome related to targeting SLAMF7. The CARs are designed without Myc tags or IgG4-Fc spacers to reduce undesirable Fc receptor interactions. The antigen recognition domain may derive from murine Luc90 or humanized Luc63 antibodies, comprising defined complementarity determining regions. The transmembrane and T cell activation domains may include human CD8α, CD28, CD3ζ, or 4-1BB domains. The invention also covers functional portions and variants that retain activity.
Claims Coverage
The patent claims include multiple inventive features focused on nucleic acids encoding CAR constructs with specificity for SLAMF7, regulatory elements, host cells, and therapeutic methods. Below are the main inventive features extracted from the independent claims.
Nucleic acid encoding a CAR with inducible caspase 9 suicide gene
A nucleic acid comprising a suicide gene and a nucleotide sequence encoding a single-chain CAR with antigenic specificity for SLAMF7. The CAR includes an antigen recognition domain comprising amino acid sequences SEQ ID NOs: 1-6, a transmembrane domain from CD8α or CD28, and a T cell activation domain. The suicide gene is an inducible caspase 9 (IC9), and the CAR nucleotide sequence is positioned 3' of the suicide gene.
Antigen recognition domain with specified variable regions
The antigen recognition domain of the CAR comprises the amino acid sequences of SEQ ID NOs: 13-14, corresponding to specific heavy and light chain variable regions derived from anti-SLAMF7 antibodies.
T cell activation domain comprising specific signaling domains
The T cell activation domain of the CAR includes intracellular T-cell signaling domains derived from one or more of human CD28, CD3-zeta, FcRγ, CD27, OX40, 4-1BB, ICOS, modified versions thereof, or any combination thereof.
Nucleic acid with cleavable linker sequence
The nucleic acid further comprises a nucleotide sequence encoding a cleavable linker positioned between the sequences encoding the CAR and the suicide gene, enabling separate protein expression.
Vector comprising the nucleic acid
A recombinant vector comprising the nucleic acid encoding the CAR and the suicide gene as described.
Host cell expressing the CAR vector
An isolated host cell, such as a T cell or a natural killer (NK) cell, that contains and expresses the recombinant vector encoding the anti-SLAMF7 CAR and suicide gene.
Population of cells comprising CAR-expressing cells
A population of cells comprising at least one host cell expressing the anti-SLAMF7 CAR from the vector.
Method of treating or preventing cancer by administering the nucleic acid
A method of treating or preventing cancer, particularly multiple myeloma, in a mammal by administering an effective amount of the nucleic acid encoding the anti-SLAMF7 CAR and suicide gene.
The claims cover nucleic acids encoding single-chain anti-SLAMF7 CARs combined with an inducible caspase 9 suicide gene, vectors containing these nucleic acids, host cells transduced with such vectors, and therapeutic methods of cancer treatment using these materials. The claims specify structural features of the CAR, including antigen recognition domains, transmembrane domains, T cell activation domains, and regulatory elements such as cleavable linkers.
Stated Advantages
Provides an alternative CAR T-cell strategy targeting SLAMF7 to treat cancers such as multiple myeloma, potentially overcoming limitations associated with BCMA-targeting CARs.
By targeting SLAMF7, which is absent from many non-hematologic tissues, it reduces or eliminates undesirable cross-reactivity and potential off-target toxicity.
Combination of the CAR with regulatory elements, such as an inducible suicide gene, offers an on-demand safety mechanism to control CAR T-cell activity and manage toxicities like depletion of normal leukocytes or severe cytokine release syndrome.
The invention's CAR design avoids use of Myc tags and IgG4-Fc spacers, reducing unwanted Fc receptor binding.
Documented Applications
Treatment or prevention of cancers expressing SLAMF7, particularly multiple myeloma in mammals including humans, using adoptive cell transfer of host cells expressing anti-SLAMF7 CARs.
Use in pharmaceutical compositions comprising host cells expressing anti-SLAMF7 CARs, optionally combined with chemotherapeutic agents.
Transient expression of anti-SLAMF7 CARs via RNA encoding the CAR for minimized toxicity and antitumor effect.
Use of anti-SLAMF7 CAR T cells in clinical trials with lymphodepleting conditioning chemotherapy and controlled administration of suicide gene activators to manage potential toxicities.
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