1, 2īispecific T-cell engager (BiTE) antibodies are a novel subclass of therapeutic single-chain antibodies.
In fact, GO given alone or in combination with other chemotherapeutics is ineffective in many patients and, as a consequence, is currently no longer commercially available in many countries. 3-5 Although this experience indicates that CD33 is a valid target for this disease, 1, 2 it is a challenging one for toxin-loaded antibodies due to its relatively low abundance, slow internalization, and drug transporter activity in AML cells. 1, 2 Recent randomized phase 3 trials have demonstrated that the CD33 antibody-drug conjugate, gemtuzumab ozogamicin (GO), improves survival for some patients with newly diagnosed AML when added to conventional chemotherapy, with benefit primarily seen for those with favorable-risk disease and, to a smaller extent, intermediate-risk disease. The most investigated target so far is CD33, a myeloid differentiation antigen found on AML blasts in most patients and, perhaps, leukemic stem cells in some. As it neither modulates CD33 expression nor is affected by ABC transporter activity, AMG 330 is highly promising for clinical exploration as it may overcome some limitations of previous CD33-targeted agents.Īcute myeloid leukemia (AML) has served as a paradigm for the therapeutic use of monoclonal antibodies because of well-defined cell-surface antigens and easy tumor accessibility.
These findings demonstrate that AMG 330 has potent CD33-dependent cytolytic activity in vitro, which can be further enhanced with other clinically available therapeutics. The epigenetic modifier drugs, panobinostat and azacitidine, increased CD33 expression in some cell lines and augmented AMG 330-induced cytotoxicity. Unlike bivalent CD33 antibodies, AMG 330 did not reduce surface CD33 expression. Using cell lines engineered to express wild-type CD33 at increased levels, we found a quantitative relationship between AMG 330 cytotoxicity and CD33 expression in contrast, AMG 330 cytotoxicity was neither affected by common CD33 single nucleotide polymorphisms nor expression of the adenosine triphosphate–binding cassette (ABC) transporter proteins, P-glycoprotein or breast cancer resistance protein.
In the presence of T cells, AMG 330 was highly active against human AML cell lines and primary AML cells in a dose- and effector to target cell ratio–dependent manner. Herein, we investigated the cellular determinants for the activity of the novel CD33/CD3-directed bispecific T-cell engager antibody, AMG 330. CD33 is a valid target for acute myeloid leukemia (AML) but has proven challenging for antibody-drug conjugates.
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