Abstract B195: Lorvotuzumab mertansine displays favorable pharmacokinetics and tumor delivery in mouse models.

Abstract

Abstract Lorvotuzumab mertansine (LM) is an antibody-drug conjugate consisting of three components: a monoclonal antibody, lorvotuzumab, that binds specifically to the CD56 antigen expressed on several types of cancers; a potent maytansinoid cell-killing agent, DM1; and a linker, SPP, that connects the two via a hindered disulfide bond. LM is currently in clinical testing for the treatment of CD56-positive tumors with encouraging results reported (Berdeja et al., ASCO 2011, Woll et al., ASCO 2011). The linker component is key parameter that may be optimized during the preclinical development of an ADC. In addition of the SPP/DM1 linker/maytansinoid combination that was selected for LM, several other combinations were evaluated including SPDB/DM4, which results in a more hindered disulfide link and SMCC/DM1, which results in an uncleavable thioether link. In in vivo studies, these alternative designs were found to offer no efficacy advantage over the SPP/DM1 design, despite the fact that they have extended time in plasma circulation. Besides efficacy, the other important determinant of therapeutic window is tolerability, posing the question of whether the more readily cleavable SPP/DM1 link results in the formation of maytansinoid catabolites likely to increase toxicity. To examine this possibility and to investigate the efficiency of tumor delivery, we conducted experiments using tumor- and non-tumor-bearing mice administered with [3H]LM or LM. We extracted, identified, and quantified the [3H]maytansinoids from tumor tissue and plasma. We also purified and characterized LM and its degradation products from mouse plasma using affinity capture with antigen immobilized on beads and LC/MS. High levels of the active maytansinoid catabolites, lysine-SPP-DM1 and DM1, were found in the tumor tissues, consistent with the robust antitumor activity of LM observed in xenograft models. The plasma samples were found to contain low levels of S-cysteinyl-DM1, suggesting that cysteine can slowly reduce LM and displace the DM1 via thiol-disulfide exchange. Observation of lorvotuzumab-SPP-cysteine from plasma by LC/MS provides further support for this exchange. We synthesized S-cysteinyl-DM1 and found it to have much lower cytotoxicity than uncharged maytansinoids in cell-based viability assays. Thus, slow degradation of LM in plasma results primarily in the release of a maytansinoid catabolite with low cytotoxic potency. The finding of highly potent maytansinoid catabolites at tumor sites in in vivo models following LM administration combined with the determination that the predominant maytansinoid found in the plasma at low levels is the relatively non-toxic S-cysteinyl-DM1 catabolite is consistent with the promising efficacy and safety profile seen with LM in the clinic. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B195.