Compositions and methods for treating cancer with anti-CD22 immunotherapy
Inventors
Orentas, Rimas J. • Schneider, Dina • Dropulic , Boro • Dimitrov, Dimiter S. • Zhu, Zhongyu
Assignees
Lentigen Technology Inc • US Department of Health and Human Services
Publication Number
US-11878052-B2
Publication Date
2024-01-23
Expiration Date
2038-10-16
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Abstract
Chimeric antigen receptors (CARs) containing CD22 antigen binding domains are disclosed. Nucleic acids, recombinant expression vectors, host cells, antigen binding fragments, and pharmaceutical compositions, relating to the CARs are also disclosed. Methods of treating or preventing cancer in a subject, and methods of making CAR T cells are also disclosed.
Core Innovation
The invention provides chimeric antigen receptors (CARs) comprising CD22 antigen binding domains, nucleic acids encoding these CARs, recombinant expression vectors, host cells such as T cells expressing the CARs, antigen binding fragments, and pharmaceutical compositions thereof. These CARs demonstrate high surface expression on transduced T cells, significant cytolysis of CD22-positive cells, and show in vivo expansion and persistence. Methods for producing these CAR T cells and using them to treat or prevent cancer in a subject are also disclosed.
The problem addressed arises from difficulties in treating B-lineage leukemias and other CD22-expressing B cell malignancies. Standard therapies, including high-dose chemotherapy and radiation, have high toxicity and risk of complications such as relapse or graft-versus-host disease. Existing CD22-targeting therapies, including antibody-drug conjugates and CARs derived from murine antibodies, show limited efficacy and immunogenicity concerns. There is a need for more effective CAR designs, especially those utilizing fully human CD22 antigen binding domains that improve T cell activation, persistence, and reduce host immune responses against the CAR.
The invention overcomes these issues by providing fully human anti-CD22 antigen binding domains incorporated into CARs with specific structural elements, including CD8-derived spacer and transmembrane domains and intracellular signaling domains such as 4-1BB and CD3 zeta. These constructs exhibit enhanced surface expression, antigen-specific cytolytic activity, cytokine secretion upon target cell engagement, and in vivo tumor control in xenograft models. The use of human-derived antigen binding domains reduces immunogenicity and enhances the durability and function of CAR T cells against CD22-expressing cancers.
Claims Coverage
The claims encompass nucleic acid molecules encoding CARs comprising CD22 antigen binding domains and associated domains, and CARs encoded thereby. There are 19 claims featuring a range of inventive features covering structural elements and sequences of the CARs.
CAR comprising human anti-CD22 antigen binding domain
An isolated nucleic acid molecule encoding a CAR comprising at least one extracellular antigen binding domain comprising a CD22 antigen binding domain selected from specific SEQ ID NOs, at least one transmembrane domain, and at least one intracellular signaling domain.
Linker or spacer domains connecting binding and signaling domains
The CD22 antigen binding domain and intracellular signaling domain are connected to the transmembrane domain via linker or spacer domains, which can be derived from the extracellular domain of CD8 or CD28.
Inclusion of leader nucleotide sequences
The nucleic acid sequence encoding the CD22 antigen binding domain is preceded by a leader nucleotide sequence encoding a leader peptide, including specific sequences (SEQ ID NOs: 190 and 191).
Specific transmembrane domains selection
The transmembrane domain is derived from proteins selected from the alpha, beta or zeta chain of the T-cell receptor, CD8, CD28, CD3 epsilon, CD45, CD4, CD5, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD83, CD86, CD134, CD137, CD154, or TNFRSF19.
Intracellular signaling domains with co-stimulatory and primary signaling functions
The intracellular signaling domain comprises a CD3 zeta intracellular domain and optionally a costimulatory domain including OX40, CD70, CD27, CD28, CD5, ICAM-1, LFA-1, ICOS, DAP10, DAP12, and 4-1BB functional signaling domains.
Specific CAR amino acid sequence embodiments
Claims include CARs encoded by nucleic acid molecules consisting of particular amino acid sequences, notably SEQ ID NO:114, encompassing the CAR structure with the human anti-CD22 binding domain.
The claims collectively cover isolated nucleic acid molecules encoding CARs with fully human CD22 antigen binding domains, incorporated with specific linker, transmembrane, and intracellular signaling domains, with prescribed sequence identities and functional domain arrangements. The CARs encoded exhibit improved specificity, expression, signaling, and therapeutic potential for treatment of CD22-expressing cancers.
Stated Advantages
The CARs exhibit high surface expression on transduced T cells.
They demonstrate a high degree of cytolysis of CD22-expressing cells.
Transduced T cells show in vivo expansion and persistence.
Use of fully human extracellular CD22 antigen binding domains reduces induction of anti-CAR immunity and elimination of CAR T cells in the host.
The CAR design allows tuning of efficacy versus toxicity by using binders with variable affinity to CD22, improving specificity to tumor cells.
Documented Applications
Treatment or prevention of cancers expressing CD22, including B-lineage leukemias such as B-ALL, DLBCL, FL, CLL, CML, AML, mantle cell lymphoma, non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma, and multiple myeloma.
Use in pharmaceutical compositions comprising human T cells expressing the CARs for treating hematologic cancers and solid tumors such as lung mesothelioma, ovarian, pancreatic cancers, head and neck cancer, breast cancer, genitourinary cancers, and others.
Methods of generating CAR T cells expressing the disclosed CARs for adoptive cell therapy.
Diagnostic methods for diseases associated with CD22 expression by contacting cells with the disclosed anti-CD22 antibodies or CARs.
Blocking CD22-dependent T cell inhibition and altering the tumor microenvironment to inhibit tumor growth.
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