IL3Rα antibody conjugates and uses thereof
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Publication Number
US-9873743-B2
Publication Date
2018-01-23
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 patent describes IL3Rα (CD123)-binding antibodies and antibody conjugates, including immunotoxins, that reduce IL3Rα-expressing cancer and cancer stem-cell populations. It also describes treatment of IL3Rα-associated hematologic cancers and other disorders using the disclosed CD123/IL3Rα-targeted antibody conjugates.
The core antibody constructs are described as single chain fragment variable (scFv) regions and variable domains with defined complementarity determining regions (CDRs) in the variable heavy (VH) and variable light (VL) domains. The nucleic acid encodes the VH and VL CDRs using explicit sequence identifiers, including specified VH domain CDR1, CDR2, and CDR3 and specified VL domain CDR1, CDR2, and CDR3.
The patent also describes antibody conjugates that include a cytotoxic agent as a conjugate component, with emphasis on Pseudomonas exotoxin A variants and related forms, including PE38 and KDEL-containing forms. It further describes IL3Rα- and CD123-targeted antibody regions paired with therapeutic payloads including macrocyclic chelators for radiometal attachment and proteinaceous cytotoxic agents configured as immunotoxins.
Claims Coverage
The independent claims are directed to four sequence-specific nucleic acid embodiments: anti-CD123 scFv-encoding nucleic acids defined by specified VH and VL CDR sequence identifiers, an anti-CD123 scFv nucleic acid comprising SEQ ID NO: 31 and SEQ ID NO: 36, and nucleic acids encoding the VH domain and VL domain of monoclonal antibody 32716 with specified SEQ ID numbers. Across these claims, the coverage is centered on explicitly specified antibody CDR/VH/VL sequence content.
ScFv CDR-encoded anti-CD123 nucleic acid
A nucleic acid that encodes a single chain fragment variable (scFv) region of an antibody that binds CD123, where the nucleic acid comprises nucleotide sequences that encode the CDRs of the VH and VL domains, and where the CDRs comprise VH domain CDR1 in SEQ ID NO: 33, VH domain CDR2 in SEQ ID NO: 34, VH domain CDR3 in SEQ ID NO: 35, VL domain CDR1 in SEQ ID NO: 38, VL domain CDR2 in SEQ ID NO: 39, and VL domain CDR3 in SEQ ID NO: 40.
SEQ ID NO: 31 and SEQ ID NO: 36 anti-CD123 scFv nucleic acid
A nucleic acid that encodes an anti-CD123 single chain fragment variable (scFv) antibody region, where the nucleic acid comprises SEQ ID NO: 31 and SEQ ID NO: 36.
Monoclonal antibody 32716 VH-domain-encoding nucleic acid
A nucleic acid that encodes the variable heavy (VH) domain of monoclonal antibody 32716, where the VH domain comprises SEQ ID NO: 32.
Monoclonal antibody 32716 VL-domain-encoding nucleic acid
A nucleic acid that encodes the variable light (VL) domain of monoclonal antibody 32716, where the VL domain comprises SEQ ID NO: 37.
Overall, the claim coverage is centered on nucleic acids encoding anti-CD123 scFv regions and the VH and VL domains of monoclonal antibody 32716, with specific CDRs or domain sequences defined by SEQ ID numbers.
Stated Advantages
The disclosed antibodies and antibody conjugates reduce IL3Rα-expressing cancer and cancer stem-cell populations.
The disclosed antibody conjugates are described as treating IL3Rα-associated hematologic cancers.
The document states performance/specification characteristics, including binding, cytotoxicity IC50, dissociation constant Kd, and k_on/k_off, for the targeted antibodies and conjugates.
Documented Applications
Treatment of IL3Rα-associated hematologic cancers.
Treatment of other disorders described as IL3Rα-associated.
Reducing IL3Rα-expressing cancer and cancer stem-cell populations.
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