M971 chimeric antigen receptors
Inventors
Orentas, Rimas J. • Pastan, Ira H. • Dimitrov, Dimiter S. • Mackall, Crystal L.
Assignees
US Department of Health and Human Services
Publication Number
US-10072078-B2
Publication Date
2018-09-11
Expiration Date
2033-09-18
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Abstract
The invention provides a chimeric antigen receptor (CAR) comprising an antigen binding domain comprising SEQ ID NOs: 1-6, a transmembrane domain, and an intracellular T cell signaling domain. Nucleic acids, recombinant expression vectors, host cells, populations of cells, antibodies, or antigen binding portions thereof, and pharmaceutical compositions relating to the CARs are 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 a chimeric antigen receptor (CAR) that includes an antigen binding domain comprising SEQ ID NOs: 1-6, a transmembrane domain, and an intracellular T cell signaling domain. The CAR specifically targets CD22, a lineage-restricted B cell antigen expressed in 60-70% of B cell lymphomas and leukemias but not present on early-stage B cells or stem cells. This allows the CAR to selectively recognize and lyse CD22-expressing cancer cells while substantially avoiding early B cells or stem cells.
The CAR includes an antigen binding domain derived from the m971 antibody, which binds a different CD22 epitope and provides improved binding compared to the HA22 immunotoxin. The CAR may comprise light and heavy chain variable regions, joined by linkers, and optionally a leader sequence. The transmembrane domain can comprise human CD8 and/or CD28 sequences, and the intracellular signaling domain can include CD28, CD137, and/or CD3 zeta signaling portions in various combinations. The invention also covers nucleic acids encoding the CARs, recombinant expression vectors, host cells expressing the CARs, pharmaceutical compositions, and methods of detecting and treating cancer with the CARs.
The problem being addressed is the unmet medical need for effective treatments for cancers, especially hematological malignancies such as B cell lymphomas and leukemias. Prior therapies like chemotherapy have limited prognosis and alternatives that specifically and effectively target cancer cells are needed. The invention seeks to provide CARs that recognize CD22 to facilitate targeted immunotherapy with reduced risk of damage to early B cells or stem cells.
Claims Coverage
The patent includes one independent claim with multiple inventive features defining the structure and composition of the chimeric antigen receptor (CAR). Below are the main inventive features as stated.
Antigen binding domain comprising SEQ ID NOs: 1-6
A CAR comprising an antigen binding domain that contains the amino acid sequences of SEQ ID NOs: 1-6, providing specificity for CD22.
Inclusion of specific transmembrane domains
The CAR includes a transmembrane domain comprising a transmembrane portion of CD8 and/or CD28, specifically amino acid sequences SEQ ID NO: 12 or 18 for CD8 and/or SEQ ID NO: 15 for CD28.
Inclusion of intracellular T cell signaling domains
The CAR intracellular T cell signaling domain comprises one or more of the intracellular signaling portions of CD28, CD137, and CD3 zeta, specifically sequences SEQ ID NO: 16 or 19 (CD28), SEQ ID NO: 13 or 20 (CD137), and SEQ ID NO: 14, 17, or 21 (CD3 zeta).
Specific CAR amino acid sequences defining second and third generation CARs
The CAR comprises any one of the amino acid sequences SEQ ID NOs: 22-24, corresponding respectively to second generation version 2 CAR (SEQ ID NO: 22), second generation version 1 CAR (SEQ ID NO: 23), and third generation CAR (SEQ ID NO: 24).
Restriction of inclusion of costimulatory molecules
The CAR's intracellular signaling domain comprises either CD28 or CD137 but not both, and it does not include more than one T cell costimulatory molecule's intracellular signaling domain.
The independent claim covers CARs with antigen binding domains specific for CD22 (SEQ ID NOs: 1-6), transmembrane domains from CD8 and/or CD28, intracellular signaling domains comprising one or more of CD28, CD137, and CD3 zeta, specific CAR amino acid sequences (SEQ ID NOs: 22-24), and limitations on costimulatory domain combinations, establishing compositions and configurations for CARs targeted to CD22 with defined structural and functional properties.
Stated Advantages
The CARs provide selective targeting and destruction of CD22-expressing cancer cells, particularly hematological malignancies, while substantially avoiding early B cells and stem cells.
Second generation CARs with CD28 transmembrane domain and signaling show improved surface expression and superior lytic activity compared to third generation CARs in vitro.
CARs containing the m971 antigen binding domain demonstrate improved binding to CD22 and enhanced immunologic responses relative to prior CARs targeting CD22.
Treatment with m971 CAR-expressing T cells reduces tumor burden and prolongs survival in animal models effectively.
Documented Applications
Treatment or prevention of cancer in a mammal by administering CARs, nucleic acids, recombinant vectors, host cells, or pharmaceutical compositions targeting CD22-expressing cancers.
Detection of the presence of cancer in a mammal via contacting a sample with CARs or related components and detecting binding complexes.
Use of CAR materials for adoptive T cell therapy targeting hematologic malignancies including B-cell leukemias and lymphomas.
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