Chimeric rabbit/human ROR1 antibodies
Inventors
Rader, Christoph • Yang, Jiahui
Assignees
US Department of Health and Human Services
Publication Number
US-9758586-B2
Publication Date
2017-09-12
Expiration Date
2031-11-30
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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 with specificity for 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 chimeric rabbit/human antibodies that bind specifically to the extracellular domain of ROR1, with defined sequences for their light and heavy chain variable domains as well as complementarity determining regions (CDRs). The invention also covers pharmaceutical compositions of these antibodies and their methods of use in diagnosis and treatment.
The antibodies of the invention can have light chains and heavy chains with at least 90% identity to specific sequences (e.g., SEQ ID NOs: 1, 3, 5 for light chains and SEQ ID NOs: 2, 4, 6 for heavy chains), or variants thereof including humanized antibodies. These antibodies have subnanomolar avidity for ROR1, bind selectively to malignant cells such as B-cell chronic lymphocytic leukemia (B-CLL) and mantle cell lymphoma (MCL) cells, and can be engineered or conjugated for enhanced therapeutic or diagnostic applications.
The problem being solved is the lack of therapeutic antibodies that specifically recognize antigens present on malignant B cells but not on normal B cells. Existing antibodies targeting antigens such as CD20 or CD52 are expressed broadly, including on normal B cells and other immune cells, leading to immunosuppression and damage to healthy tissues. There is a need for antibodies with good efficacy that exhibit minimal binding to non-diseased cells, hence reducing undesirable immunogenicity and side effects.
Claims Coverage
The patent includes multiple independent claims directed to antibodies specific for the extracellular domain of human ROR1 and pharmaceutical compositions and kits comprising such antibodies. The main inventive features relate to antibody specificity, defined sequence identities, conjugation to synthetic molecules, and uses in compositions and kits.
Antibody specificity for human ROR1 with defined CDR sequences
An antibody having specificity for the extracellular domain of human ROR1 comprising complementarity-determining regions (CDRs) with specific sequences as set forth in SEQ ID NOs: 31-48, including three alternative sets of CDRs.
Antibody variable domain sequence identity thresholds
The antibody comprises light and heavy chain variable domains having at least 95% sequence identity to specific amino acid sequences (SEQ ID NO: 1 and 2; SEQ ID NO: 3 and 4; or SEQ ID NO: 5 and 6).
Antibody comprising exact variable domain sequences
The antibody comprises light chain and heavy chain variable domains consisting of the amino acid sequences of SEQ ID NOs: 1 and 2; SEQ ID NOs: 3 and 4; or SEQ ID NOs: 5 and 6 respectively.
Antibody conjugation to synthetic molecules
The antibody can be conjugated to synthetic molecules including those comprising a transmembrane region and intracellular T cell receptor (TCR) signaling domain, labels, cytotoxic agents such as toxins, therapeutic radioisotopes, liposomes, or other antibodies such as rituximab or bevacuzimab.
Pharmaceutical composition comprising the antibody
A pharmaceutical composition comprising a therapeutically effective amount of the isolated antibody and a pharmaceutically acceptable carrier.
Kit comprising the isolated antibody
A kit that includes the isolated antibody and optionally immunoassay buffers and other components suitable for carrying out therapeutic or diagnostic methods.
The claims collectively cover antibodies with defined ROR1 specificity through sequence and CDR identity, their conjugates with synthetic molecules including toxins and labels, pharmaceutical compositions comprising these antibodies, and kits including the antibodies, thus providing comprehensive protection for the antibodies and their medical and diagnostic uses.
Stated Advantages
The antibodies exhibit selective binding to malignant B cells with minimal binding to normal B cells, reducing immunosuppression and damage to healthy tissues.
The antibodies have subnanomolar affinity and avidity for human ROR1, allowing effective targeting of ROR1-expressing tumors.
The antibodies can be engineered or conjugated to synthetic molecules for enhanced therapeutic functionality including targeted cytotoxicity or diagnostic imaging.
Documented Applications
Treatment of disorders associated with elevated ROR1 expression such as B-cell chronic lymphocytic leukemia (B-CLL), mantle cell lymphoma (MCL), Burkitt lymphoma, renal cell carcinoma, colon cancer, and breast cancer.
Diagnostic methods to detect altered levels of ROR1 in samples or subjects, including screening for and monitoring tumors expressing ROR1.
Use of antibodies conjugated to labels or contrast agents for imaging and detection of ROR1-expressing tumors.
Generation of genetically engineered T cells expressing ROR1-specific antibodies as chimeric antigen receptors (CARs) or T-bodies for adoptive immunotherapy.
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