B cell surface reactive antibodies
Inventors
Rader, Christoph • Baskar, Sivasubramanian • Bishop, Michael R. • Samija, Ivan • Suschak, Jessica M.
Assignees
US Department of Health and Human Services
Publication Number
US-8877199-B2
Publication Date
2014-11-04
Expiration Date
2030-05-12
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Abstract
The invention relates to antibodies that are reactive to the cell surface of CD19+ B cells, including B-cell chronic lymphocytic leukemia (B-CLL) cells, and compositions and methods for using such antibodies, including in the diagnosis and treatment of disorders associated with CD19+ B cells, such as B-CLL.
Core Innovation
The invention provides isolated antibodies with specificity for cell surface markers found on certain CD19+ B cells, including B-cell chronic lymphocytic leukemia (B-CLL) cells. These antibodies have B-CLL cell surface reactivity and comprise light chain and heavy chain variable domains with at least 90% identity to selected sequences, or both. The invention further covers antibodies comprising one or more complementarity determining regions (CDRs) with specific sequences or variants thereof. Pharmaceutical compositions comprising such antibodies and methods of using these antibodies for treating diseases associated with elevated levels of CD19+ B cells, such as B-CLL, are also provided.
The antibodies can be full-length, fragments, monoclonal, recombinant, chimeric, or humanized, preferably fully human and may be of any isotype. They can be produced by various expression systems and can be conjugated to synthetic molecules including therapeutic agents, radioisotopes, labels, or used to engineer immune cells such as T-cells expressing chimeric antigen receptors (T-bodies or CARs). The invention also covers methods of inhibiting growth of CD19+ B cells, methods of treatment by administering these antibodies or engineered cells, and diagnostic methods for detecting altered levels of CD19+ B cells reactive with the antibodies.
The invention addresses the challenge that current antibody therapies for B-CLL target antigens on both malignant and normal B cells and other immune cells, leading to immunosuppression and damage to healthy tissues. Existing approaches do not distinguish cell surface from intracellular antigens effectively. The invention provides antibodies that preferentially target malignant B cell surface antigens with good efficacy and minimal immunogenicity and damage to non-diseased cells.
Claims Coverage
The patent includes 2 independent claims encompassing antibody compositions specific for B-CLL cell surface reactivity, characterized by variable domain sequences or complementarity determining regions (CDRs).
Antibody with specific light and heavy chain variable domain sequences
An isolated antibody having B-CLL cell surface reactivity comprising one of four pairs of light chain variable domain and heavy chain variable domain sequences exactly as set forth in SEQ ID NOs:1 and 18; 9 and 26; 12 and 31; or 14 and 33.
Antibody defined by specific complementarity determining regions (CDRs)
An isolated antibody with B-CLL cell surface reactivity comprising sets of CDRs exactly as set forth: (i) CDRL1 SEQ ID NO:3, CDRL2 SEQ ID NO:5, CDRL3 SEQ ID NO:7, CDRH1 SEQ ID NO:20, CDRH2 SEQ ID NO:22, CDRH3 SEQ ID NO:24; (ii) CDRL1 SEQ ID NO:3, CDRL2 SEQ ID NO:5, CDRL3 SEQ ID NO:7, CDRH1 SEQ ID NO:28, CDRH2 SEQ ID NO:30, CDRH3 SEQ ID NO:24; or (iii) CDRL1 SEQ ID NO:3, CDRL2 SEQ ID NO:16, CDRL3 SEQ ID NO:7, CDRH1 SEQ ID NO:28, CDRH2 SEQ ID NO:30, CDRH3 SEQ ID NO:24.
Antibody framework regions inclusion
Antibodies of claim 2 also include VH framework regions SEQ ID NO:23 and SEQ ID NO:25, and VL framework regions SEQ ID NO:4 and SEQ ID NO:8 in combination with the specified CDRs.
Antibody isotype and fragment forms
The antibodies can be any of various isotypes including IgA1, IgA2, IgD, IgE, IgG (subtypes 1-4), IgM, or fragments such as F(ab)2, Fv, scFv, Fab, dsFv, diabodies, T-bodies, bispecific or bivalent antibodies.
Conjugation to synthetic molecules
Antibodies can be conjugated to synthetic molecules, including cytotoxic agents, therapeutic radioisotopes, or labels, and engineered as T-bodies comprising transmembrane and intracellular TCR signaling domains.
Pharmaceutical composition
Pharmaceutical compositions comprising a therapeutically effective amount of the antibody and a pharmaceutically acceptable carrier.
Diagnostic kit
A kit comprising the antibody and optionally immunoassay buffers or conjugated labels suitable for detection of CD19+ B cells.
The claims cover isolated antibodies with defined variable domain sequences or CDRs that specifically bind B-CLL cell surface antigens, including various antibody forms and conjugations, pharmaceutical compositions, and diagnostic kits.
Stated Advantages
Provides antibodies that preferentially target malignant B cell surface antigens with good efficacy.
Minimizes immunogenicity and damage to non-diseased cells compared to existing therapies.
Enables sensitive detection of serum antibodies with B-CLL cell surface reactivity.
Documented Applications
Diagnosis and treatment of disorders associated with CD19+ B cells such as B-cell chronic lymphocytic leukemia (B-CLL).
Use as therapeutic antibodies or pharmaceutical compositions for inhibiting growth of CD19+ B cells in vitro or in vivo.
Development of genetically engineered T-cells (T-bodies or CARs) expressing the antibody for adoptive cell therapy of B-CLL.
Diagnostic detection of altered levels of B-CLL cells in samples or subjects using immunoassays such as flow cytometry and ELISA.
Screening and monitoring of subjects for presence, progression, or therapeutic response of B-CLL by detecting antibody-reactive CD19+ B cells.
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