Precision ‘re’arming of CD33 antibodies

In this issue of Blood, Kung Sutherland et al report on the preclinical activity of SGN-CD33A, a humanized anti-CD33 antibody conjugated to a pyrrolobenzodiazepine (PBD) dimer via a protease-cleavable linker, against acute myeloid leukemia (AML) cells in vitro and in vivo.¹ 

At this time, there is a void in the field of antibody–drug conjugates (ADC) targeting CD33 as a therapeutic option for treatment of AML after the voluntary withdrawal of gemtuzumab ozogamicin (GO) from the market.

Even though CD33 is an antigen that is both considered to be expressed in more committed myeloid precursors^2,3  and is not present in AML stem cells, the clinical relevance of CD33 as a target is validated by survival benefit with GO in subgroups of patients with AML in randomized clinical trials.^4-6  The reliable efficacy of drug conjugation with antibody and the greater stability of conjugate to avoid the exposure of non-target-expressing tissue to drugs can improve CD33 ADCs as therapeutic agents. The PBD dimer released after protease cleavage of SGN-CD33A causes DNA cross-linking and is capable of inducing cell cycle arrest and apoptosis. Engineered cysteine moieties at linker attachment sites allow more precise PBD dimer loading of antibody, thus improving predictability of payload delivery. The activity of SGN-CD33A requires CD33 expression, but its activity does not correlate with levels of CD33 surface expression. In vitro studies with SGN-CD33A showed approximately 3-fold more potency than GO shows against primary AML cells. What makes SGN-CD33A potentially interesting is that this ADC appears to have activity irrespective of the multidrug resistance phenotype and p53 status of AML cells. Additional in vivo studies using immune-competent isogeneic mouse models of disseminated AML with relevant translocations/mutations and variable p53 backgrounds are needed to add valuable information to the current report. In addition, data regarding levels of “naked” PBD dimer in plasma after infusions are important, as this may have relevance with regard to nonspecific toxicity.

There is a distinct need in the field for CD33-based ADCs to quickly fill the void left by the withdrawal of GO from the market, and the rapid preclinical and clinical development of agents such as SGN-CD33A is needed.