Human monoclonal antibodies specific for CD22
Inventors
Dimitrov, Dimiter S. • Xiao, Xiaodong • Pastan, Ira H.
Assignees
US Department of Health and Human Services
Publication Number
US-8591889-B2
Publication Date
2013-11-26
Expiration Date
2029-04-01
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Abstract
Disclosed herein are isolated human monoclonal antibodies that specifically bind human CD22 with a dissociation constant (Kd) of 25 nM or less. Nucleic acids encoding these antibodies, expression vectors including these nucleic acid molecules, and isolated host cells that express the nucleic acid molecules are also disclosed. The antibodies can be used to detect human CD22 in a sample. In some cases, CD22 is soluble CD22. Methods of diagnosing a B-cell malignancy, or confirming a B-cell malignancy diagnosis, are disclosed herein that utilize these antibodies. Methods of treating a subject with a B-cell malignancy are also disclosed.
Core Innovation
Disclosed are isolated human monoclonal antibodies that specifically bind human CD22 with a dissociation constant (Kd) of about 25 nM or less. These antibodies can be in various formats including Fab, IgG1, and scFv, and can be used to detect human CD22 in samples, including soluble forms of CD22. Nucleic acids encoding these antibodies, expression vectors including these nucleic acids, and isolated host cells expressing such nucleic acids are also provided. Immunoconjugates comprising these human monoclonal antibodies conjugated to therapeutic agents or labels are described.
The problem addressed arises from the expression of CD22 on mature B-cells and in 60-70% of B-cell lymphomas and leukemias, making CD22 an attractive immunotherapy target. Existing mouse monoclonal antibodies directed against CD22 elicit a human anti-murine antibody (HAMA) response, which involves allergic reactions and increased clearance of the therapeutic antibody from serum. Attempts to humanize antibodies have not fully overcome these limitations. Therefore, there is a need for fully human antibodies that specifically bind CD22 with high affinity for effective diagnosis and treatment of B-cell malignancies. These human antibodies avoid the HAMA response and improve clinical applicability.
Claims Coverage
The patent includes multiple claims with one independent claim directed to a human monoclonal antibody specifically binding CD22, and additional claims directed to compositions, immunoconjugates, methods of treating B-cell malignancies, and diagnostic methods. The main inventive features from the independent claims are summarized below.
Human monoclonal antibody specifically binding human CD22 with defined binding affinity and sequence features
An isolated human monoclonal antibody that specifically binds human CD22 with a binding affinity of about 20 nM or less, wherein the heavy chain comprises amino acids 26-33, 51-59, and 97-106 of SEQ ID NO: 1, and the light chain comprises amino acids 27-32, 50-52, and 89-98 of SEQ ID NO: 2; optionally the antibody comprises the full sequences of SEQ ID NOs: 1 and 2, and can be of the IgG isotype.
Compositions containing the human monoclonal antibody
Compositions comprising the isolated human monoclonal antibody in a pharmaceutically acceptable carrier.
Immunoconjugates comprising the human monoclonal antibody and effector molecules
Isolated immunoconjugates comprising the human monoclonal antibody and an effector molecule, which can be a toxin (such as Pseudomonas exotoxin) or a detectable label, and compositions thereof.
Methods of treating B-cell malignancies using the antibody or immunoconjugates
Methods of treating subjects having CD22-expressing B-cell malignancies by administering a therapeutically effective amount of the antibody or immunoconjugate conjugated to an agent that inhibits growth or kills malignant B-cells. The B-cell malignancies include non-Hodgkin's lymphoma, hairy cell leukemia, and chronic lymphocytic leukemia.
Methods of detecting and confirming B-cell malignancies by antibody binding
Methods to determine the presence of a CD22-expressing B-cell malignancy by contacting a sample from a subject with the human monoclonal antibody, detecting binding to malignant B-cells, and determining malignancy presence. Also, methods of confirming a diagnosis by detecting increased binding to soluble CD22 in blood samples compared to controls, optionally using a labeled antibody or a secondary antibody recognizing the primary antibody.
Nucleic acid molecules encoding the antibody and engineered host cells
Isolated nucleic acid molecules encoding the human monoclonal antibody heavy and light chains (including sequences of SEQ ID NOs: 7 and 8), expression vectors containing these nucleic acids operably linked to promoters, and host cells transformed with these nucleic acids for expression.
The claims collectively cover the isolated fully human anti-CD22 monoclonal antibodies with specific sequence and binding affinity features, pharmaceutical compositions including these antibodies, immunoconjugates conjugated to therapeutic or diagnostic moieties, therapeutic methods for B-cell malignancies, diagnostic methods and kits for detecting and confirming CD22-expressing B-cell malignancies, and nucleic acid and vector inventions enabling antibody production.
Stated Advantages
The antibodies are fully human, eliminating the human anti-murine antibody (HAMA) response associated with mouse monoclonal antibodies, thus improving safety and serum persistence in patients.
The antibodies specifically bind CD22 with high affinity (dissociation constant about 25 nM or less), providing effective targeting and detection capabilities.
The antibodies and conjugates are useful both for therapeutic applications, including treatment of B-cell malignancies, and diagnostic applications, such as detection and confirmation of B-cell malignancy diagnosis.
Documented Applications
Use of the human monoclonal antibodies and immunoconjugates for treatment of B-cell malignancies, including non-Hodgkin's lymphoma, hairy cell leukemia, chronic lymphocytic leukemia, Burkitt's lymphoma, small lymphocytic lymphoma, primary effusion lymphoma, diffuse large B-cell lymphoma, splenic marginal zone lymphoma, MALT lymphoma, and B-cell prolymphocytic leukemia.
Diagnostic methods employing the antibodies to detect and confirm B-cell malignancies by binding to cell surface CD22 or soluble CD22 in biological samples, such as blood or serum.
Use of antibodies in immunoassays (e.g., ELISA, flow cytometry, immunohistochemistry) for detecting CD22 expression in biological samples.
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