Anti-human ROR1 antibodies
Inventors
Rader, Christoph • Baskar, Sivasubramanian
Assignees
US Department of Health and Human Services
Publication Number
US-9316646-B2
Publication Date
2016-04-19
Expiration Date
2030-04-23
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Abstract
The invention relates to antibodies having specificity for human ROR1, compositions thereof, and methods for using such antibodies, including in the diagnosis and treatment of disorders associated with aberrant ROR1 expression.
Core Innovation
The invention provides isolated antibodies that have specificity for the extracellular domain of human receptor tyrosine kinase-like orphan receptor 1 (ROR1), which is selectively expressed on the surface of malignant cells, including B-cell tumors and other cancers. These antibodies include variants comprising heavy and light chains with at least 90% sequence identity to specified sequences (SEQ ID NO: 1 and SEQ ID NO: 2) and complementarity determining regions (CDRs) selected from stated sequences or minor variants thereof. The antibodies can be full-length, fragments, chimeric, humanized, or recombinant versions with various isotypes and modifications.
The problem being addressed arises from the lack of therapeutic antibodies that specifically recognize antigens present on malignant B cells but absent on normal B cells. Existing antibodies, such as rituximab and alemtuzumab, target antigens like CD20 and CD52 which are expressed not only on malignant but also on normal immune cells, leading to immunosuppression and damage to healthy tissues. Therefore, there is a need for antibodies with good efficacy that minimize binding and damage to non-diseased cells by selectively targeting cancer-associated antigens like ROR1.
The invention also encompasses pharmaceutical compositions containing these anti-ROR1 antibodies and methods of their use in treating diseases associated with aberrant or elevated ROR1 expression, such as B-cell lymphoma, renal cell carcinoma, colon cancer, and breast cancer. Additionally, methods include diagnostic uses for detecting cells with altered ROR1 levels. The antibody can be conjugated to synthetic molecules including cytotoxic agents or labels for improved therapeutic or diagnostic purposes.
Claims Coverage
The patent includes multiple independent claims directed to antibodies with specificity for the extracellular domain of human ROR1, their compositions, conjugates, pharmaceutical formulations, and kits. The main inventive features cover the antibody sequences, structures, conjugations, and therapeutic uses.
Antibody specificity for human ROR1 extracellular domain CDRs
An antibody comprising complementarity determining regions (CDRs) with the specific sequences SEQ ID NO: 4, 6, 8, 11, 13, and 15, conferring specificity for the extracellular domain of human ROR1.
Heavy and light chain variable domain sequence identity
An antibody having a heavy chain variable domain with at least 95% sequence identity to SEQ ID NO: 1 and a light chain variable domain with at least 95% sequence identity to SEQ ID NO: 2, which together define the antibody's specificity.
Antibody isotype and fragment types
The antibody is selected from various classes and fragments including IgA, IgD, IgE, IgG (including synthetic IgG), IgM, and antibody fragments such as F(ab)2, Fv, scFv, dsFv, diabody, and bivalent antibodies.
Conjugation to synthetic molecules
Antibodies conjugated to synthetic molecules such as cytotoxic agents, therapeutic radioisotopes, labels for detection, or engineered as T-bodies with transmembrane and intracellular TCR signaling domains for immunotherapeutic applications.
Pharmaceutical compositions and kits
Pharmaceutical compositions comprising the antibodies and pharmaceutically acceptable carriers, as well as diagnostic or therapeutic kits containing the antibody and optional buffers or labels.
Conjugates with cytotoxic agents
Conjugates of the antibody with cytotoxic agents such as Pseudomonas exotoxin A (PE38) for targeted cell killing.
Antibodies with specificity for additional antigens
Antibodies engineered to have specificity for ROR1 and additional tumor antigens or antigens promoting activation or targeting of cytotoxic effector cells for enhanced therapeutic efficacy.
The claims cover anti-ROR1 antibodies defined by particular variable domain sequences and CDR compositions, diverse antibody forms and conjugates, pharmaceutical compositions and kits, as well as methods of targeting ROR1-expressing cells therapeutically and diagnostically. The inventive features emphasize specificity for ROR1, modular antibody constructs, and conjugation strategies.
Stated Advantages
The antibodies exhibit high specificity for malignant cells expressing ROR1, minimizing binding to normal tissues and thereby reducing potential immunosuppression and off-target damage.
The invention provides therapeutic agents capable of selectively targeting B-cell lymphomas and other cancers associated with elevated ROR1 expression, offering potentially improved efficacy.
The antibodies can be conjugated to cytotoxic agents or imaging labels to enhance therapeutic or diagnostic utility.
The invention enables diagnostic assays to detect altered ROR1 levels for detecting or monitoring cancers.
Documented Applications
Treatment of diseases or conditions associated with elevated ROR1 expression, including B-cell chronic lymphocytic leukemia (B-CLL), mantle cell lymphoma (MCL), Burkett's lymphoma, renal cell carcinoma, colon cancer (e.g., colon adenocarcinoma), and breast cancer (e.g., breast adenocarcinoma).
Diagnostic detection of cells with altered ROR1 levels in biological samples such as plasma or tissue from subjects at risk for or suffering from ROR1-associated cancers.
Screening and monitoring of subjects for ROR1-expressing tumors using labeled anti-ROR1 antibodies and imaging modalities like CT, MRI, ultrasound, and nuclear medicine.
Pharmaceutical compositions for administering anti-ROR1 antibodies alone or conjugated to therapeutic agents or radioisotopes to subjects in need.
Genetically engineered T-cells expressing anti-ROR1 antibodies as chimeric antigen receptors (T-bodies or CARs) for adoptive cell therapy.
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