The mechanism of action of calicheamicin, a DNA-damaging agent that, following intracellular activation, binds to DNA in the minor groove and introduces double-strand DNA breaks, leading to G2/M arrest and subsequent cell death, is fundamentally different from the tubulin-binding class of cytotoxics targeting the mitotic spindle, which represent the most common class of payloads for antibody-drug conjugates (ADCs) currently undergoing clinical development.
Spindle poisons that target tubulin, including auristatins and maytansines, are most effective against rapidly proliferating cells.
In contrast, calicheamicin, a member of a highly potent enediyne class of DNA-damaging cytotoxic natural products, induces DNA double-strand breaks and apoptosis independent of cell cycle progression. Such properties may be advantageous when targeting malignant cells that are not markedly different in their proliferation status compared to normal cells.
In an article published in Molecular immunology, Boris Shor, Hans-Peter Gerber and Puja Sapra review calicheamicin conjugates, with a particular focus on the preclinical- and clinical development of inotuzumab ozogamicin (Pfizer), targeting the CD22 antigen expressed on a large variety of hematologic malignancies.
In pre-clinical experiments, inotuzumab ozogamicin potently induced tumor regressions in models of non-Hodgkin’s lymphoma (NHL), either alone or in combination with the anti-CD20 antibody rituximab (Rituxan®; Genentech and MabThera®, Roche).
Promising anti-tumor responses were observed in early stage clinical trials, where inotuzumab ozogamicin was administered either as single agent or in combination with rituximab. Consistent with the cell cycle independent mechanism of action of the calicheamicin payload, high rates of complete responses were observed in less aggressive forms of lymphomas, including follicular lymphoma (FL) and relapsed, diffuse large B-cell lymphoma (DLBCL). Inotuzumab ozogamicin is currently in phase III clinical trials in acute lymphocytic leukemia (ALL).
In this article, the authors focus their review on the pre-clinical and clinical data generated with this compound in NHL and to outline future focus areas for pre-clinical- and clinical research of inotuzumab ozogamicin, and the calicheamicin class of antibody-drug conjugates more generally.
Published in: Molecular Immunology