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Publication Number
US-12187802-B2
Publication Date
2025-01-07
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 single chain fragment variable (scFv) molecules encoded by a nucleic acid. The scFv comprises a variable heavy (VH) domain and a variable light (VL) domain that bind the alpha subunit of the interleukin-3 receptor (IL3Rα), and the binding is defined by complementarity determining regions (CDRs) in the VH and VL domains. The disclosed CDRs comprise VH domain CDR1 of SEQ ID NO: 3, VH domain CDR2 of SEQ ID NO: 4, VH domain CDR3 of SEQ ID NO: 5, VL domain CDR1 of SEQ ID NO: 8, VL domain CDR2 of SEQ ID NO: 9, and VL domain CDR3 of SEQ ID NO: 10.
The disclosure further specifies the scFv through additional SEQ ID NOs at the nucleotide and amino-acid level, including the DNA nucleotide sequence of SEQ ID NO: 1 for the VH domain, the DNA nucleotide sequence of SEQ ID NO: 6 for the VL domain, and amino acid sequences SEQ ID NO: 2 and SEQ ID NO: 7. The document also includes an isolated engineered mammalian cell line, including a human cell line, that expresses the anti-CD123 scFv.
The document describes IL3Rα as broadly expressed in leukemia subpopulations and not detectable on normal hematopoietic progenitors. Based on IL3Rα targeting, the invention includes therapeutic approaches for reducing IL3Rα-expressing cancer cell and cancer stem cell populations, including naked antibodies, engineered fragments or variants, and antibody conjugates such as immunotoxins that link IL3Rα antibodies to cytotoxic or anticellular agents.
Claims Coverage
The claims cover one independent inventive feature centered on an anti-CD123 scFv defined by specific VH and VL CDRs that bind IL3Rα. Dependent claims further specify nucleotide and amino-acid sequence identities and extend coverage to an isolated engineered mammalian cell line expressing the scFv, including a human cell line variant.
Il3rα-binding anti-cd123 scfv defined by specified vh and vl cdrs
An anti-CD123 single chain fragment variable (scFv) encoded by a nucleic acid comprising nucleotide sequences that encode the complementarity determining regions (CDRs) of a variable heavy (VH) domain and a variable light (VL) domain, wherein the VH and VL domains bind the alpha subunit of the interleukin-3 receptor (IL3Rα), and wherein the CDRs comprise VH domain CDR1 of SEQ ID NO: 3, VH domain CDR2 of SEQ ID NO: 4, VH domain CDR3 of SEQ ID NO: 5, VL domain CDR1 of SEQ ID NO: 8, VL domain CDR2 of SEQ ID NO: 9, and VL domain CDR3 of SEQ ID NO: 10.
Specified vh nucleotide encoding for the anti-cd123 scfv
The anti-CD123 scFv is defined such that the nucleotide sequences encoding the VH domain comprise the DNA nucleotide sequence of SEQ ID NO: 1.
Specified vl nucleotide encoding for the anti-cd123 scfv
The anti-CD123 scFv is defined such that its VL domain is encoded by the DNA nucleotide sequence of SEQ ID NO: 6.
Specified vh and vl amino-acid sequences for the anti-cd123 scfv
The anti-CD123 scFv is defined such that its VH and VL domains are encoded by nucleotide sequences specifying amino acid sequences SEQ ID NO: 2 and SEQ ID NO: 7, respectively.
Engineered isolated mammalian cell line expressing the anti-cd123 scfv
A mammalian cell line that is isolated and engineered to express the anti-CD123 scFv.
Human mammalian cell line expressing the anti-cd123 scfv
The mammalian cell line is a human cell line.
Overall, the claim scope is centered on an anti-CD123 scFv defined by specific VH and VL CDR identities that bind IL3Rα, with dependent claims further fixing VH/VL nucleotide and amino-acid identities via SEQ ID NOs and extending coverage to an engineered isolated mammalian cell line expressing the scFv.
Stated Advantages
Improved activity is described for a KDEL-containing variant.
Therapeutic targeting is directed to diseases where cells overexpress IL-3 receptor subunits, including IL-3Rα/CD123 or IL-3Rβ.
Monitoring of cancer cells and immune/hematologic indicators is described, along with monitoring cancer stem cells using phenotypic markers and assays.
Reduces IL3Rα-expressing cancer cell and cancer stem cell populations.
IL3Rα is broadly expressed in leukemia subpopulations and is not detectable on normal hematopoietic progenitors.
Documented Applications
Therapeutic targeting of autoimmune disorders and allergic diseases is described where cells overexpress IL-3 receptor subunits.
Treatment for cancers is described, including cancers expressing IL-3Rα/CD123 or IL-3Rβ, with monitoring of cancer stem cells using phenotypic markers and assays.
Example evaluation includes anti-CD123 monoclonal antibodies and derived scFv-PE38 immunotoxins on TF-1 and AML cell lines, including binding and cytotoxicity readouts.
Bone marrow purging and autologous stem cell transplant are described using anti-IL-3Rα antibody conjugates, including threshold reduction of IL-3Rα+ cells.
Therapeutic use for reducing IL3Rα-expressing cancer cell and cancer stem cell populations, including hematological cancers.
Use in hematological cancers such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).
Therapeutic regimens including prophylaxis, treatment, relapse prevention, and relapse management.
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