anti-CD123/TOP1i antibody-drug conjugate AZD9829

An antibody-drug conjugate (ADC) consisting of a monoclonal antibody against the interleukin-3 (IL3)-receptor alpha chain (CD123; IL-3RA) conjugated to a topoisomerase-1 inhibitor (TOP1i), with potential antineoplastic activity. Upon administration of anti-CD123/TOP1i ADC AZD9829, the antibody moiety targets and binds to the cell surface antigen CD123 expressed on tumor cells. Upon binding and internalization, the TOP1i moiety is released, binds to TOP1 and stabilizes cleaved DNA-TOP1 complexes. This prevents DNA re-ligation, induces irreversible DNA strand breaks, prevents DNA repair, and leads to cycle arrest and apoptosis specifically in tumor cells expressing CD123. CD123 regulates the proliferation, survival and differentiation of hematopoietic cells. CD123 is overexpressed on a variety of cancers, including myeloid leukemia, and increased expression of CD123 on leukemic stem cells is associated with poor prognosis.