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-9279019-B2
Publication Date
2016-03-08
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 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, including soluble CD22. Furthermore, the invention includes methods of diagnosing a B-cell malignancy or confirming a B-cell malignancy diagnosis using these antibodies, as well as methods of treating subjects with a B-cell malignancy.
CD22 is a 135 kDa sialoglycoprotein expressed on mature B-cells and involved in B-cell activation and cell adhesion. It is expressed in 60-70% of B-cell lymphomas and leukemias, making it an attractive target for immunotherapy. Existing mouse monoclonal antibodies targeting CD22 induce human anti-murine antibody (HAMA) responses, which can lead to allergic reactions and faster clearance of the antibodies. There is a need for fully human antibodies that specifically bind CD22 with high affinity for use in cancer diagnosis and treatment, but producing such antibodies is difficult since human antigens are generally recognized as self.
The invention addresses this need by providing fully human monoclonal antibodies that bind human CD22 with high affinity, thereby avoiding HAMA responses. These antibodies can be formulated into compositions and immunoconjugates, which can be used for research, diagnostic, and therapeutic purposes, including the treatment of various B-cell malignancies such as non-Hodgkin's lymphoma and chronic lymphocytic leukemia. The antibodies can detect both membrane-bound and soluble forms of CD22, facilitating diagnosis, confirmation, or monitoring of B-cell malignancies.
Claims Coverage
The claims include one independent claim directed to a monoclonal antibody specific for human CD22 and its composition forms, nucleic acids, and immunoconjugates, covering main inventive features related to antibody structure, binding affinity, and conjugation.
Specific monoclonal antibody composition
A monoclonal antibody specifically binding human CD22 comprising a heavy chain portion with amino acid residues 26-35, 53-61, and 100-113 of SEQ ID NO: 3, and a light chain portion with amino acid residues 27-32, 50-52, and 89-97 of SEQ ID NO: 4.
Antibody variable region configuration
The heavy chain variable (VH) region and/or the light chain variable (VL) region of the antibody include sequences present within SEQ ID NOs: 3 and 4 respectively, allowing the antibody to specifically bind human CD22.
Antibody formats included
The antibody can be in multiple formats including Fab, single chain variable fragment (scFv), or IgG antibody.
Pharmaceutical composition
Compositions comprising the CD22-specific monoclonal antibody in a pharmaceutically acceptable carrier.
Immunoconjugate formation
Immunoconjugates comprising the monoclonal antibody linked to effector molecules such as toxins or detectable labels.
Toxin choice in immunoconjugates
Use of Pseudomonas exotoxin as the toxin moiety in immunoconjugates.
Detectable labels in immunoconjugates
Use of fluorescent, enzymatic, or radioactive labels as detectable moieties in immunoconjugates.
Nucleic acid molecules encoding antibody
Nucleic acid molecules encoding the monoclonal antibody, including sequences of SEQ ID NOs: 9 and 10 or portions thereof.
Expression systems
Expression vectors including the nucleic acid molecules and host cells transformed with such nucleic acids capable of expressing the monoclonal antibody or immunoconjugates.
The claims encompass fully human monoclonal antibodies specific to human CD22 defined by particular heavy and light chain amino acid sequences, their variable regions, antibody forms, pharmaceutical compositions containing them, immunoconjugates with toxins or labels (notably Pseudomonas exotoxin), and nucleic acid constructs and host cells for producing these antibodies, collectively providing comprehensive coverage of the invention's key features.
Stated Advantages
Avoidance of human anti-murine antibody (HAMA) response by using fully human antibodies specific for CD22.
High binding affinity (Kd about 25 nM or less) to human CD22 enabling effective diagnosis and treatment of B-cell malignancies.
Capability to detect both cell surface and soluble forms of CD22, enhancing diagnostic accuracy.
Versatility of antibody formats (Fab, scFv, IgG) and capacity for immunoconjugate formation, allowing diverse therapeutic and diagnostic applications.
Documented Applications
Use of the antibodies for diagnosing and confirming diagnosis of B-cell malignancies by detecting increased binding to CD22 or soluble CD22 in biological samples.
Treatment of subjects diagnosed with B-cell malignancies by administering therapeutically effective amounts of the antibodies or immunoconjugates comprising the antibodies.
Monitoring of soluble CD22 levels in subjects to assess tumor burden and effectiveness of cancer therapies.
Use as research reagents to study the biology of CD22-expressing cancers.
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