Anti-CD276 polypeptides, proteins, and chimeric antigen receptors
Inventors
Orentas, Rimas J. • Zhu, Zhongyu • Mackall, Crystal L. • Dimitrov, Dimiter S. • St. Croix, Bradley • Saha, Saurabh
Assignees
National Institutes of Health NIH • Biomed Valley Discoveries Inc • US Department of Health and Human Services
Publication Number
US-11512138-B2
Publication Date
2022-11-29
Expiration Date
2034-03-24
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Abstract
Polypeptides and proteins that specifically bind to and immunologically recognize CD276 are disclosed. Chimeric antigen receptors (CARs), anti-CD276 binding moieties, 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 polypeptides and proteins comprising antigen binding domains of anti-CD276 antibodies that specifically recognize and bind to CD276. The polypeptides and proteins may elicit an antigen-specific immune response against CD276, which is expressed or overexpressed in a variety of human tumors including pediatric solid tumors and adult carcinomas such as neuroblastoma, Ewing's sarcoma, rhabdomyosarcoma, prostate, ovarian, colorectal, and lung cancers. The invention also encompasses chimeric antigen receptors (CARs) comprising these anti-CD276 antigen binding domains, nucleic acids encoding the polypeptides and proteins or CARs, recombinant expression vectors, host cells, cell populations, and pharmaceutical compositions relating thereto.
The background describes an unmet need in cancer treatment, particularly for solid tumors, where existing therapies such as chemotherapy may have poor prognosis. The invention aims to address this unmet need by providing novel anti-CD276 binding polypeptides, proteins, and CARs for detecting and treating cancer in mammals. These inventive materials are designed to enable specific targeting and destruction of CD276-expressing cancer cells, to reduce or eliminate cancer cells, and to facilitate immune cell infiltration and enhanced anti-cancer responses.
Claims Coverage
The claims include multiple inventive features covering polypeptides, proteins, chimeric antigen receptors (CARs), nucleic acids, expression vectors, host cells, and cell populations, as well as their use in cancer treatment.
Polypeptides comprising heavy and light chains binding CD276 with leader sequences
Polypeptides comprising heavy and light chains with amino acid sequences SEQ ID NOs: 1-6, 11-16, or 20-25 that bind CD276, and further comprising a leader amino acid sequence (e.g., SEQ ID NO: 60, 61, or 62).
Proteins comprising paired heavy and light chains binding CD276 with leader sequences
Proteins comprising a first polypeptide chain with heavy chain sequences SEQ ID NOs: 1-3, 11-13, or 20-22 and a second polypeptide chain with light chain sequences SEQ ID NOs: 4-6, 14-16, or 23-25 that bind CD276, and further comprising a leader amino acid sequence.
Polypeptides comprising linkers
Polypeptides further comprising linker amino acid sequences, preferably SEQ ID NO: 115, linking variable regions or domains.
Chimeric antigen receptors with anti-CD276 antigen binding domains
CARs comprising: (a) an antigen binding domain formed by heavy and light chains comprising SEQ ID NOs: 1-6, 11-16, or 20-25 binding CD276; (b) a leader amino acid sequence; (c) a transmembrane domain (including CD8 and/or CD28 sequences, e.g., SEQ ID NOs: 29, 30, or 31); and (d) an intracellular T cell signaling domain comprising one or more of CD28 (SEQ ID NOs: 32, 35), CD137 (SEQ ID NOs: 33, 37), and CD3 zeta (SEQ ID NOs: 34, 36, 38).
Nucleic acids encoding the polypeptides and CARs
Nucleic acids comprising nucleotide sequences encoding the polypeptides or CARs, including sequences such as SEQ ID NOs: 63, 64, 79, 81, 83, and 140.
Recombinant expression vectors and host cells
Recombinant expression vectors comprising the nucleic acids and host cells transformed or transfected with such vectors.
Populations of cells comprising host cells expressing the inventive polypeptides or CARs
Populations of cells comprising at least one isolated host cell expressing the polypeptides or CARs.
The claims collectively cover the composition of anti-CD276 polypeptides and proteins with leader and linker sequences, their encoding nucleic acids and recombinant vectors, chimeric antigen receptors incorporating these antigen binding domains with specific transmembrane and intracellular signaling domains, as well as host cells and cell populations expressing these CARs or polypeptides, directed to binding CD276 for cancer detection and treatment.
Stated Advantages
Specifically recognize and bind to CD276, enabling targeted detection and treatment of CD276-expressing cancer cells.
Elicit an antigen-specific immune response that may target and destroy cancer cells, reduce tumor burden, facilitate immune infiltration, and enhance anti-cancer responses.
Chimeric antigen receptors allow for non-MHC-restricted antigen recognition, potentially overcoming tumor escape mechanisms.
Modified CAR domains (such as immunoglobulin constant domains and preferred transmembrane/intracellular signaling sequences) may improve binding affinity and functional mimicry of native T cell receptors.
Documented Applications
Treatment or prevention of cancer in a mammal, including various pediatric and adult solid tumors and carcinomas characterized by CD276 expression or overexpression.
Detection of cancer presence in a mammal by contacting a sample with the anti-CD276 polypeptides, proteins, CARs, or binding moieties and detecting complexes indicative of cancer cells.
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