SGN-CD123A Drug Description

Acute myeloid leukemia or AML is an aggressive, life-threatening disease with at least 33,000 newly diagnosed cases in the U.S. and Europe each year, and those patients have few effective treatment options Survival for patients with AML remain poor, representing a major unmet medical need requiring the development of future treatment options. [1]

The majority of AML blasts express CD123, the alpha subunit of the IL-3 receptor (IL-3RA).  CD123 is  frequently observed in some leukemic disorders and may contribute to the proliferation, survival and differentiation of leukemic cells. [2]

CD123 is also a marker for minimal residual disease (MRD). Researchers have associated an elevated expression of CD123 on leukemic stem cells, blasts and poor prognosis.  Furthermore, CD123 included on leukemic stem cells, which are difficult to kill, may be responsible for high rates of relapse even following intensive therapy.[1]

Normal hematopoietic stem cells have limited expression of CD123. Hence, based on these observations, CD123 has been identified as therapeutic target in AML.

Figure 1.0: SGN-CD123A is an investigational agent being developed by Seattle Genetics. The safety and efficacy of this novel agents has not yet been established.

A novel CD123-directed immunoconjugate or antibody-drug conjugate SGN-CD123A, which consist of a humanized anti-CD123 antibody conjugated to a two molecules of a highly potent DNA crosslinking agent called a pyrrolobenzodiazepine (PBD) dimer, via a stable, protease-cleavable dipeptide linker, is being developed by Seattle Genetics.  An engineered cysteine on each heavy chain attaching the PBD dimer to the antibody allows uniform drug loading of approximately two PBD dimers per antibody.

Fluorescence microscopy studies have confirmed that the investigational SGN-CD123A is rapidly internalized and traffics to lysosomes within hours of binding to CD123-positive AML cells. Following uptake of the antibody-drug-conjugate SGN-CD123A induces DNA damage as measured by dose-and time-dependent increases in the phosphorylation of histone 2AX (γH2AX) and cell death associated with G2-M cell cycle arrest, caspase-3 activity, formation of cleaved poly ADP-ribose polymerase, and DNA fragmentation in target cells.

Reference:
[1] Kung Sutherland MS, Walter RB, Jeffrey SC, Burke PJ, Yu C, Kostner H, Stone I, et al. SGN-CD33A: a novel CD33-targeting antibody-drug conjugate using a pyrrolobenzodiazepine dimer is active in models of drug-resistant AML.Blood. 2013 Aug 22;122(8):1455-63. doi: 10.1182/blood-2013-03-491506. Epub 2013 Jun 14.
[2] Testa U, Pelosi E, Frankel A. CD 123 is a membrane biomarker and a therapeutic target in hematologic malignancies. Biomark Res. 2014; 2: 4. | Published online 2014 Feb 10. doi: 10.1186/2050-7771-2-4 | PMCID: PMC3928610


Last Editorial Review: September 10, 2017