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-10543263-B2
Publication Date
2020-01-28
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 present invention discloses chimeric antigen receptors (CARs) containing CD22 antigen binding domains, as well as nucleic acids, recombinant expression vectors, host cells (e.g., T cells) expressing these CARs, antigen binding fragments, and pharmaceutical compositions related thereto. The disclosed CARs exhibit high surface expression on transduced T cells, a high degree of cytolysis of CD22-expressing cells, and an ability for in vivo expansion and persistence of the transduced T cells. Methods of treating or preventing cancer in a subject using these CARs, and methods of making CAR T cells, are also provided.
The problem being addressed is the limited effectiveness and toxicities of current treatments for B-lineage leukemias and other B cell malignancies, including high-dose chemotherapy, radiation, and antibody-based therapies. Issues such as high toxicity, risk of relapse, secondary malignancies, and graft versus host disease motivate the need for better therapeutic alternatives. Although some CD22 targeting therapies exist, including antibodies and antibody-drug conjugates, their efficacy and safety profiles are limited. Many existing anti-CD22 CAR constructs utilize murine-derived antigen binding domains that lead to limited in vivo expansion and persistence, and may provoke host immune responses against the CAR T cells. There is an urgent need for novel compositions and methods that specifically target CD22 with high efficacy and persistence, while minimizing adverse effects.
The invention provides fully human anti-CD22 antigen binding domains incorporated into CARs that demonstrate superior surface expression on T cells, specific recognition and cytolytic activity against CD22-expressing tumor cells, and better in vivo expansion and persistence compared to murine-derived CARs. The use of fully human antigen binding domains reduces anti-CAR immunity and improves functional activity, thus overcoming previous shortcomings. Multiple CAR constructs containing various newly identified human CD22 binding domains have been designed and tested, showing specific tumor cell killing and cytokine production, with some constructs showing favorable activity profiles suitable for clinical application.
Claims Coverage
The patent claims cover a method of treating hematological cancer using T cells expressing chimeric antigen receptors (CARs) that target CD22, with various structural and functional features of the CARs.
Inclusion of fully human CD22 antigen binding domains in CARs
The CAR comprises at least one extracellular antigen binding domain with a CD22 antigen binding domain selected from specified amino acid sequences (SEQ ID NOs: 2, 12, 22, 32, 42, 52, 62, 72, 82, 92, 102, 112, 122, 132, 142, 152, 162, or 172) ensuring specific targeting of hematological cancer cells.
Incorporation of specific transmembrane domains
The CAR includes transmembrane domains derived from alpha, beta or zeta chains of proteins such as T-cell receptor, CD8, CD28, CD3 epsilon, CD45, CD4, CD5, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, or CD154 to facilitate proper CAR expression and function.
Use of linker or spacer domains connecting CAR domains
The CD22 antigen binding domain and intracellular signaling domain(s) are connected to the transmembrane domain via linker or spacer domains, preferably derived from the extracellular domain of CD8 or CD28, to optimize CAR structure and activity.
Inclusion of leader nucleotide sequence encoding a leader peptide
The encoded extracellular CD22 antigen binding domain is preceded by a leader nucleotide sequence that directs proper protein processing and expression.
Inclusion of intracellular signaling domains including CD3 zeta and costimulatory domains
The CAR intracellular domain contains a CD3 zeta signaling domain in combination with costimulatory domains such as OX40, CD70, CD27, CD28, CD5, ICAM-1, LFA-1, ICOS, DAP10, DAP12, or 4-1BB, which enhance T cell activation and persistence.
Method of treating hematological cancers including leukemia, lymphoma, and multiple myeloma
The method employs administering T cells expressing the described CARs to subjects with hematological cancers such as chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), mantle cell lymphoma, non-Hodgkin's lymphoma (NHL) or Hodgkin's lymphoma.
The claims collectively define a method of treating hematological cancers by administering T cells transduced with CARs that specifically target CD22 using fully human antigen binding domains, optimized transmembrane, linker, and signaling domains to achieve effective and specific anti-tumor activity with improved persistence and reduced immunogenicity.
Stated Advantages
The CARs exhibit high surface expression on transduced T cells, leading to robust targeting of CD22-positive malignant cells.
The use of fully human CD22 antigen binding domains avoids immune responses against murine components, improving in vivo persistence and expansion of CAR T cells.
The CARs demonstrate specific and potent cytolytic activity against CD22-expressing tumors, reducing off-target effects.
Design of CARs with various linkers, transmembrane, and intracellular signaling domains allows tuning of efficacy versus toxicity, improving therapeutic profiles for different disease burdens.
Documented Applications
Treatment or prevention of hematological cancers including leukemias (CLL, ALL, AML, CML), lymphomas (mantle cell lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma), and multiple myeloma.
Generation of CAR T cells for adoptive cell immunotherapy targeting CD22-expressing B cell malignancies in human subjects.
Diagnosis or prognosis of diseases associated with CD22 expression using the anti-CD22 antibodies or CARs.
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