Methods of treatment of CD123 overexpressing disorders
The present disclosure relates to protein molecules that specifically bind to CD123, which may have at least one humanized or human CD123-binding domain. Such molecules are useful for the treatment of cancer. The protein molecule binding to CD123 may have a second binding domain that binds to another target. In one embodiment, multi-specific polypeptide molecules bind both CD123-expressing cells and the T-cell receptor complex on T-cells to induce target-dependent T-cell cytotoxicity, activation, and proliferation. The disclosure also provides pharmaceutical compositions comprising the CD123-binding polypeptide molecules, nucleic acid molecules encoding these polypeptides and methods of making these molecules.
1. A method for treating a disorder in a subject, wherein said disorder is characterized by overexpression of CD123, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a recombinant polypeptide comprising a CD123 binding domain and a CD3 binding domain;
wherein the recombinant polypeptide comprises the amino acid sequence of SEQ ID NO:130 or SEQ ID NO:132; and
wherein the administration of the pharmaceutical composition induces reduced cytokine levels in the subject as compared to administration of (a) a dual affinity re-targeting antibody comprising the CD123 binding domain and the CD3 binding domain of the recombinant polypeptide; or (b) a bispecific T-cell engager molecule comprising the CD123 binding domain and the CD3 binding domain of the recombinant polypeptide.
2. The method of claim 1 , wherein the disorder is a cancer.
3. The method of claim 2 , wherein the cancer is acute myeloid leukemia (AML), B-lymphoid leukemia, blastic plasmocytoid dendritic neoplasm (BPDCN), hairy cell leukemia, acute lymphoblastic leukemia, refractory anemia with excess blasts, myelodysplastic syndrome, chronic myeloid leukemia or Hodgkin's lymphoma.
4. The method of claim 1 , wherein the subject was previously treated with a CD123-binding molecule different from the polypeptide, and wherein the subject experienced an adverse event after the previous treatment.
5. The method of claim 4 , wherein the adverse event was excessive cytokine release.
6. The method of claim 1 , wherein the pharmaceutical composition comprises a dimeric protein comprising two identical copies of the recombinant polypeptide.
7. The method of claim 1 , wherein the cytokine levels are levels of IFN-γ, TNF-α, IL-6, IL-2, IL-8, IL-10, IL-17, GM-CSF, IL-4, IL-12, IL-13 or IL-1β, or any combination thereof.
8. The method of claim 1 , wherein the cytokine levels are levels of IFN-γ, IL-2, TNF-α and IL-10.
9. The method of claim 1 , wherein the cytokine levels are measured in an in vitro activated T cell assay.