Anti-CD276 chimeric antigen receptors
Inventors
Mackall, Crystal L. • Cui, Yongzhi Karen
Assignees
US Department of Health and Human Services
Publication Number
US-10562952-B2
Publication Date
2020-02-18
Expiration Date
2036-09-09
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Abstract
Chimeric antigen receptors (CARs) that specifically bind to and immunologically recognize CD276 are disclosed. Related nucleic acids, recombinant expression vectors, host cells, populations of cells, and pharmaceutical compositions relating to the polypeptides and proteins are also 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) that specifically bind to and immunologically recognize CD276, also known as B7-H3. These CARs comprise an antigen binding domain with amino acid sequences of SEQ ID NOs: 1-6, a transmembrane domain, and an intracellular T cell signaling domain. The invention includes related nucleic acids, recombinant expression vectors, host cells expressing the CARs, populations of such cells, and pharmaceutical compositions thereof.
The CARs utilize the antigen binding domain of antibodies such as MGA271 and variants thereof, allowing target-specific recognition of CD276-expressing cancer cells. The CAR design includes transmembrane domains from CD8 or CD28 and intracellular signaling domains including CD28, 4-1BB (CD137), and CD3ζ, which enable effective T cell activation upon antigen binding.
The problem addressed by the invention is the unmet need for new cancer treatments, particularly for solid tumors, as existing treatments like chemotherapy often provide poor prognoses. CD276 is overexpressed on various human tumors, including pediatric solid tumors and adult carcinomas. By targeting CD276 with CARs, the invention aims to provide methods to detect, treat, or prevent cancer by eliciting antigen-specific immune responses against these cancers.
Claims Coverage
The patent presents one independent claim focusing on a chimeric antigen receptor comprising a specific amino acid sequence and its related compositions and methods. The main inventive features include the composition of the CAR, detection methods, and therapeutic methods involving cancers expressing CD276.
Chimeric antigen receptor comprising the amino acid sequence of SEQ ID NO: 12
A CAR molecule that includes the antigen binding domain and signaling domains specifically defined by the amino acid sequence SEQ ID NO: 12, conferring specific recognition of CD276.
Nucleic acid encoding the CAR
A nucleic acid molecule comprising a nucleotide sequence encoding the CAR of SEQ ID NO: 12, enabling recombinant expression.
Recombinant expression vector comprising the nucleic acid
A recombinant vector that contains the nucleic acid encoding the CAR, facilitating its introduction and expression in host cells.
Pharmaceutical composition comprising the CAR and pharmaceutically acceptable carrier
A formulation including the CAR along with a pharmaceutically acceptable carrier for administration.
Method of detecting cancer using the CAR
A method involving contacting a sample from a mammal with the CAR to form a complex, and detecting this complex to indicate the presence of cancer expressing CD276.
Method of treating or preventing cancer using the CAR
Administering the CAR in an effective amount to a mammal to treat or prevent cancer that expresses CD276, including specific cancers like solid tumors and carcinomas.
The independent claim covers the CAR with a defined amino acid sequence and extends to nucleic acids, expression vectors, pharmaceutical compositions, methods of detection of CD276-expressing cancer, and methods to treat or prevent such cancers using the CAR.
Stated Advantages
The CARs provide robust expansion of transduced T cells without evidence of early exhaustion or apoptosis.
These CARs facilitate specific binding to CD276, enabling effective immune responses against a range of CD276-expressing cancers.
CAR T cells expressing the invention's CAR demonstrate enhanced secretion of cytokines like IFN-γ and TNF-α, indicative of potent antitumor activity.
The CAR T cells persist in vivo and exhibit superior tumor control and survival benefits in animal models compared to other CAR constructs or controls.
Documented Applications
Detecting the presence of cancer in a mammal by contacting samples with the CAR and detecting complexes formed with CD276-expressing cells.
Treating or preventing cancer in mammals by administering an effective amount of the CAR, particularly for cancers expressing CD276.
Targeted immunotherapy against various cancers, including but not limited to solid tumors, carcinomas, neuroblastoma, Ewing's sarcoma, rhabdomyosarcoma, prostate cancer, ovarian cancer, colorectal cancer, and lung cancer.
Use in pharmaceutical compositions for administration to subjects in need for cancer immunotherapy.
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