IL3Rα antibody conjugates and uses thereof
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Publication Number
US-9518119-B2
Publication Date
2016-12-13
Expiration Date
Abstract
The present invention provides antibodies that bind to the IL-3 receptor alpha subunit alpha (Il3Rα) chain, and compositions comprising such antibodies. The present invention provides methods for inhibiting or reducing an IL3Rα-expressing cell population, the methods comprising contacting a population of IL3Rα-expressing cells (e.g., cancer cells and/or cancer stem cells) with an antibody that binds to IL3Rα. The present invention also provides antibody conjugates comprising an antibody that binds to an IL3Rα chain linked to a cytotoxic agent or anticellular agent and compositions comprising such conjugates. The present invention also provides methods for preventing, treating and/or managing a disorder associated with IL3Rα-expressing cells (e.g., a hematological cancer), the methods comprising administering to a subject in need thereof an antibody that binds to IL3Rα.
Core Innovation
The invention relates to anti-CD123 (IL3Rα) antibody-binding single chain fragment variable (scFv) antibody regions and nucleic acids encoding those scFv regions. The nucleic acid encodes CDRs of the variable heavy (VH) domain and the variable light (VL) domain that bind CD123, with CDRs defined by specified SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5 for the VH domain and SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10 for the VL domain.
A further aspect of the invention defines nucleic acids that encode an anti-CD123 scFv antibody region comprising SEQ ID NO: 1 and SEQ ID NO: 6. These scFv-encoding nucleic acids can be provided as part of a fusion protein that includes a second protein, where the fusion protein architecture links the CD123-binding scFv region to an additional protein payload.
The nucleic acids are also specified for particular antibody regions, including a nucleic acid encoding the variable heavy (VH) domain of monoclonal antibody 26292 comprising SEQ ID NO: 2 and a nucleic acid encoding the variable light (VL) domain of monoclonal antibody 26292 comprising SEQ ID NO: 7. The overall target is reducing IL3Rα-expressing cell populations, including cancer stem cells and hematologic cancers such as acute myeloid leukemia (AML) and related disorders.
The invention also relates to IL3Rα antibody conjugates comprising IL3Rα-binding antibody constructs conjugated to cytotoxic proteinaceous agents and radiometal chelator components. The conjugates retain IL3Rα binding kinetics while delivering cytotoxic payloads to IL3Rα-expressing cells, and include immunotoxin and immunoconjugate architectures in which an IL3Rα antibody, including scFv and dsFv formats, is associated with engineered cytotoxic proteinaceous agents and radiometal radiotherapeutic components.
Claims Coverage
The partial content provides four independent claim groups for the scFv and monoclonal antibody sequence disclosures and four independent claim groups for IL3Rα-directed conjugates and compositions. Collectively, the independent claims define sequence-specific nucleic acids encoding CD123-binding scFv antibody regions and specific VH/VL domains, and IL3Rα-binding antibody constructs conjugated to cytotoxic proteinaceous agents and radiometal chelator components.
Anti-CD123 scFv CDR-defined nucleic acid encoding VH and VL CDRs
A nucleic acid that encodes an anti-CD123 scFv antibody region, comprising nucleotide sequences that encode the complementarity determining regions (CDRs) of the VH domain and the VL domain, wherein the CDRs comprise the VH domain CDR1 presented in SEQ ID NO: 3, the VH domain CDR2 presented in SEQ ID NO: 4, the VH domain CDR3 presented in SEQ ID NO: 5, the VL domain CDR1 presented in SEQ ID NO: 8, the VL domain CDR2 presented in SEQ ID NO: 9, and the VL domain CDR3 presented in SEQ ID NO: 10.
Anti-CD123 scFv nucleic acid comprising SEQ ID NO: 1 and SEQ ID NO: 6
A nucleic acid that encodes an anti-CD123 scFv antibody region, wherein said nucleic acid comprises SEQ ID NO: 1 and SEQ ID NO: 6.
Monoclonal antibody 26292 VH-domain nucleic acid encoding SEQ ID NO: 2
A nucleic acid that encodes the variable heavy (VH) domain of monoclonal antibody 26292, wherein said VH domain comprises SEQ ID NO: 2.
Monoclonal antibody 26292 VL-domain nucleic acid encoding SEQ ID NO: 7
A nucleic acid that encodes the variable light (VL) domain of monoclonal antibody 26292, wherein said VL domain comprises SEQ ID NO: 7.
IL3Rα-binding antibody conjugates with cytotoxic payloads
IL3Rα-binding antibody constructs conjugated to cytotoxic proteinaceous agents, designed to retain IL3Rα binding kinetics while delivering cytotoxic payloads to IL3Rα-expressing cells.
Pseudomonas exotoxin A engineered payloads
Use of Pseudomonas exotoxin A variants, including PE35, PE37, PE38, and PE40, with defined alterations, including incorporation of IL3Rα antibody or scFv into defined PE regions and use of KDEL and KDEL variants.
Radiometal chelator conjugates
IL3Rα-targeted conjugates that include radiometal chelator components and macrocyclic chelators such as DOTA, coupled to antibody constructs via linker molecules.
Alternative cytotoxic and therapeutic payloads
Payload options that include plant toxins, fungal toxins, bacterial toxins, additional proteinaceous cytotoxic entities, nanoparticles, and other therapeutic agents.
Across the independent claims, the core claim coverage is directed to sequence-defined nucleic acids encoding anti-CD123 (IL3Rα) scFv antibody regions via specified CDRs and via specified scFv constituent sequences, additional nucleic acids encoding the VH domain or VL domain of monoclonal antibody 26292, and IL3Rα-directed conjugates and compositions with cytotoxic or radiotherapeutic payloads, including engineered PE variants and radiometal chelator-linked constructs.
Stated Advantages
The conjugates are designed to retain IL3Rα binding kinetics while delivering cytotoxic payloads to IL3Rα-expressing cells.
The disclosure includes therapeutic contexts in which efficacy is monitored by reduction or monitoring of cancer stem cell and cancer cell populations.
Sequence-conservative variants and identity ranges are described while maintaining the intended cytotoxic function of the toxin payload.
Documented Applications
Reducing IL3Rα-expressing cell populations, including cancer stem cells and hematologic cancers such as acute myeloid leukemia (AML) and related disorders.
Targeting diseases associated with IL3Rα expression, including plasmacytoid dendritic cell-characterized diseases such as HIV/herpes/CMV, autoimmune disorders, allergies, and a broad range of cancers.
Autologous bone marrow purging (IL-3Rα-expressing cells).
Monitoring approaches for cancer stem cells/cancer cells and related hematologic parameters, including cancer stem cell phenotypes and CD123 expression and cytotoxicity.
Therapeutic use in cancer, inflammatory, autoimmune, and allergic disorders, including myeloid leukemia and related conditions, NK blastic leukemia/plasmacytoid dendritic cell lymphoma, and HIV/CMV/herpes contexts as IL3Rα-expressing diseases.
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