Camptothecins exist in a pH-dependent equilibrium between the active, closed
lactone and the inactive open-carboxylate forms. Several previous reports underscore the need for
lactone stabilization in generating improved camptothecins, and indeed, such designs have been incorporated into
antibody-drug conjugates containing this drug. Here, we demonstrate that
lactone stabilization is not necessary for
camptothecin-based ADC efficacy. We synthesized and evaluated
camptothecin SN-38 drug linkers that differed with respect to
lactone stability and released
SN-38 or the hydrolyzed open-
lactone form upon cleavage from the antibody carrier. An α-hydroxy
lactone-linked
SN-38 drug linker preserved the closed-
lactone ring structure, while the
phenol-linked version allowed conversion between the closed-
lactone and open-carboxylate structures. The in vitro cytotoxicity, pharmacokinetic properties, and in vivo efficacy in the L540cy
Hodgkin's lymphoma model of the corresponding ADCs were found to be indistinguishable, leading us to conclude that
camptothecin-based
antibody-drug conjugates possess pronounced activity regardless of the
lactone state of the bound drug. This is most likely a result of ADC processing within acidic intracellular vesicles, delivering
camptothecin in its active closed-
lactone form.