IRTA2 antibodies and methods of use
Inventors
Pastan, Ira • Ise, Tomoko • Xiang, Laiman • Nagata, Satoshi
Assignees
DEPARTMENT OF HEALTH AND HUMAN SERVICES GOVERNMENT OF United States, THE, Secretary of • US Department of Health and Human Services
Publication Number
US-7999077-B2
Publication Date
2011-08-16
Expiration Date
2025-09-22
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Antibodies that specifically bind the extracellular domain of IRTA2 are disclosed herein. In one embodiment, these antibodies do not specifically bind IRTA1, IRTA3, IRTA4, or IRTA5. In one example, the antibodies are humanized antibodies. The antibodies can be conjugated to effector molecules, including detectable labels, radionucleotides, toxins and chemotherapeutic agents. The antibodies that specifically bind IRTA2 are of use to detect B cell malignancies, such as hairy cell leukemia and non-Hodgkin's lymphoma. These antibodies that specifically bind IRTA2 are also of use to treat B cell malignancies that express IRTA2, such as hairy cell leukemia and non-Hodgkin's lymphoma.
Core Innovation
Monoclonal antibodies that specifically bind the extracellular domain of IRTA2 are disclosed, with embodiments where these antibodies do not specifically bind IRTA1, IRTA3, IRTA4, or IRTA5. These antibodies can be conjugated to effector molecules including detectable labels, radionucleotides, toxins, and chemotherapeutic agents. The antibodies are useful to detect and treat B cell malignancies, such as hairy cell leukemia (HCL) and non-Hodgkin's lymphoma.
The problem being addressed arises from chromosomal abnormalities involving the 1q21-q23 regions frequently observed in B cell malignancies, including B cell non-Hodgkin's lymphoma and multiple myeloma. These abnormalities target genes largely unknown prior to this invention, but cloning translocation breakpoints identified IRTA1 and IRTA2 as candidate genes. IRTA2 is a cell surface receptor normally expressed in mature B cells with deregulated expression in multiple myeloma and Burkitt lymphoma cell lines exhibiting 1q21 abnormalities. Given these structural rearrangements' frequency, IRTA1 and IRTA2 are implicated as critical in the pathogenesis of these diseases. There remains a need for recombinant toxins and immunotherapy agents for treating B cell malignancies.
Claims Coverage
The patent contains one independent claim covering an isolated monoclonal antibody or antigen-binding fragment thereof, including specified CDR sequences, that specifically binds an IRTA2 epitope. The claims include features regarding framework regions, conjugation to effector molecules, and methods of detection.
Monoclonal antibody with defined CDR sequences specifically binding IRTA2 extracellular domain
An isolated monoclonal antibody or antigen-binding fragment comprising a light chain with L-CDR1 (amino acids 24-35 of SEQ ID NO:4), L-CDR2 (amino acids 51-57 of SEQ ID NO:4), and L-CDR3 (amino acids 90-98 of SEQ ID NO:4); and a heavy chain with H-CDR1 (amino acids 31-35 of SEQ ID NO:3), H-CDR2 (amino acids 50-67 of SEQ ID NO:3), and H-CDR3 (amino acids 100-107 of SEQ ID NO:3), wherein the antibody specifically binds the IRTA2 amino acid sequence spanning residues 287-565 of SEQ ID NO:13.
Framework region variations
The monoclonal antibody or antigen-binding fragment can comprise a human framework region or a murine framework region.
Antigen binding fragments
The antibody antigen-binding fragment can be an Fv, Fab, or F(ab')2 fragment.
Conjugation to effector molecules
The monoclonal antibody or antigen-binding fragment can be conjugated to an effector molecule, including toxins.
Effector molecule examples
Effector molecules include ricin A, abrin, diphtheria toxin or a subunit thereof, Pseudomonas exotoxin or a portion thereof, saporin, restrictocin or gelonin.
Pseudomonas exotoxin variants
Pseudomonas exotoxin effector molecules can include those with amino acid sequences of SEQ ID NO:53 (PE40), SEQ ID NO:54 (PE38), SEQ ID NO:55 (PE38 KDEL), SEQ ID NO:56 (PE38REDL), or SEQ ID NO:57 (PE4E).
Therapeutic composition
A pharmaceutically acceptable composition comprising a therapeutically effective amount of the disclosed antibody.
Method of detecting soluble IRTA2 protein
A method for detecting the soluble IRTA2 protein (amino acids 287-565 of SEQ ID NO:13) in a sample using the isolated monoclonal antibody or antigen-binding fragment, forming an antibody-protein complex and detecting its presence.
Labeling and assay formats for detection
The monoclonal antibody or antigen-binding fragment or humanized forms may be labeled, for example with fluorescent labels. Detection methods include enzyme-linked immunosorbent assay (ELISA).
The claims cover isolated monoclonal antibodies or antigen-binding fragments with defined CDR sequences that specifically bind the extracellular domain (amino acids 287-565) of IRTA2, including humanized or murine frameworks, their conjugation to various effector molecules including toxins, pharmaceutical compositions thereof, and methods for detecting soluble IRTA2 in samples using labeled antibodies in assays such as ELISA.
Stated Advantages
The antibodies disclosed specifically bind IRTA2 with high affinity and selectivity and can differentiate IRTA2 from other IRTA family members.
The antibodies can detect IRTA2 expression on malignant B cells including hairy cell leukemia and non-Hodgkin's lymphoma cells.
The antibodies, including immunotoxins, provide a means to treat B cell malignancies expressing IRTA2.
Development of immunoassays for detecting soluble IRTA2, which may serve as a biomarker for B cell malignancies.
Documented Applications
Detection of B cell malignancies such as hairy cell leukemia and non-Hodgkin's lymphoma by immunofluorescence, flow cytometry (FACS), and ELISA using antibodies specific to IRTA2.
Treatment of B cell malignancies that express IRTA2 using antibodies that specifically bind IRTA2, potentially conjugated to cytotoxic effector molecules such as toxins (immunotoxins).
Use of antibodies conjugated to detectable labels (e.g., fluorescent, radioactive) for diagnostic assays including ELISA and immunohistochemistry.
Measurement and monitoring of soluble IRTA2 levels in patient serum as a tumor marker for hematological malignancies.
Interested in licensing this patent?