Dual specific anti-CD22-anti-CD19 chimeric antigen receptors
Inventors
Fry, Terry J. • Mackall, Crystal L. • Orentas, Rimas J. • HASO, Waleed • Qin, Haiying
Assignees
US Department of Health and Human Services
Publication Number
US-10738116-B2
Publication Date
2020-08-11
Expiration Date
2036-03-18
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Abstract
The invention provides dual specific chimeric antigen receptors (CARs) having antigenic specificity for CD19 and CD22. Nucleic acids, recombinant expression vectors, host cells, populations of cells, 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 dual specific chimeric antigen receptors (CARs) having antigenic specificity for both CD19 and CD22. The CAR comprises an anti-CD22 antigen binding domain, an anti-CD19 antigen binding domain, a hinge domain, a transmembrane domain, and an intracellular T cell signaling domain. Related nucleic acids, recombinant expression vectors, host cells, populations of cells, and pharmaceutical compositions concerning the CARs are also disclosed. Methods of detecting the presence of cancer and methods for treating or preventing cancer in mammals using these dual specific CARs are described.
Cancer, particularly hematological malignancies, remains a significant public health challenge with often poor prognosis despite advances such as chemotherapy. There exists an unmet need for novel and effective cancer treatments. The problem addressed by this invention is to improve treatment options for cancers, especially those expressing CD19 and CD22 antigens, by providing CARs capable of dual antigen targeting to reduce cancer cell escape and improve therapeutic potency.
The dual specificity of the inventive CARs allows them to specifically bind and immunologically recognize two distinct antigens, CD19 and CD22, eliciting an immune response upon binding either antigen. This dual specificity may advantagesously provide increased potency compared to CARs specific for only one antigen. It may reduce or prevent cancer relapse due to loss of antigen expression, for example, cases where cancer cells lose CD19 expression after treatment with anti-CD19 CARs. Additionally, the dual specific CARs may extend the treatable patient population by targeting cancer cells expressing either or both antigens.
Claims Coverage
The patent contains multiple independent claims covering the dual specific CAR, nucleic acids encoding the CAR, recombinant expression vectors, host cells, populations of cells expressing the CAR, pharmaceutical compositions comprising these cells, and methods of treating hematological malignancies using T cells expressing the CAR.
Dual specific chimeric antigen receptor comprising anti-CD22 and anti-CD19 binding domains
A CAR having antigenic specificity for both CD19 and CD22, comprising an anti-CD22 antigen binding domain, an anti-CD19 antigen binding domain, a hinge domain, a transmembrane domain, and an intracellular T cell signaling domain, with the CAR comprising the amino acid sequence of SEQ ID NO: 23 or SEQ ID NO: 24.
CD8 transmembrane and hinge domains in the CAR
The CAR comprises a CD8 transmembrane domain and a CD8 hinge domain, wherein the CD8 transmembrane domain comprises the amino acid sequence of SEQ ID NO: 26 and the CD8 hinge domain comprises the amino acid sequence of SEQ ID NO: 33.
Intracellular T cell signaling domains including 4-1BB and CD3 zeta
The intracellular T cell signaling domain of the CAR comprises a 4-1BB intracellular T cell signaling sequence, preferably the amino acid sequence of SEQ ID NO: 27, and a CD3 zeta intracellular T cell signaling sequence, preferably the amino acid sequence of SEQ ID NO: 28.
Pharmaceutical compositions comprising cells expressing the dual specific CAR
Pharmaceutical compositions containing a population of cells that express the dual specific anti-CD19-anti-CD22 CAR and a pharmaceutically acceptable carrier.
Nucleic acids encoding the dual specific CAR
Nucleic acids comprising nucleotide sequences encoding the CAR, specifically sequences of SEQ ID NO: 31 or 32.
Recombinant expression vectors comprising nucleic acids encoding the CAR
Recombinant expression vectors containing nucleic acids encoding the dual specific CAR.
Host cells and populations of cells expressing the CAR
Isolated host cells, including populations of cells, that comprise the recombinant expression vectors encoding the dual specific CAR.
Methods of treating hematological malignancies with T cells expressing the CAR
Methods comprising administering to a human patient a population of T cells expressing a nucleic acid encoding the dual specific CAR in an amount effective to treat a hematological malignancy.
The claims cover the dual specific CAR comprising anti-CD22 and anti-CD19 antigen binding domains with specific domains and sequences, nucleic acids and vectors encoding the CAR, host cells expressing the CAR, pharmaceutical compositions thereof, and methods of treating hematological malignancies using T cells expressing the CAR.
Stated Advantages
Provides a greater potency compared to CARs that target only one antigen (either CD19 or CD22).
Reduces or prevents cancer cell escape due to loss of expression of one antigen by the cancer cell.
Potentially reduces or prevents relapse observed in patients treated with CARs targeting only CD19 that lose CD19 expression.
Increases the treatable patient population by targeting cancer cells expressing either CD19 or CD22 or both.
By eliciting an antigen-specific response against CD22 and CD19, facilitates targeting and destruction of cancer cells expressing these antigens and enhances anti-cancer immune responses.
Documented Applications
Methods of detecting the presence of cancer in a mammal by contacting a sample from the mammal with the CARs or related materials and detecting complexes indicative of cancer.
Methods of treating or preventing cancer, including hematological malignancies such as acute lymphocytic leukemia, lymphoma, chronic lymphocytic leukemia, B-cell malignancies, and others characterized by CD19 and/or CD22 expression, by administering the CARs or cells expressing them.
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