Abstract C105: Pediatric Preclinical Testing Program (PPTP) Stage 1 evaluation of the CD56-targeting antibody-drug conjugate lorvotuzumab mertansine.
Authors: Houghton Peter J. , Maris John M. , Keir Stephen T. , Lock Richard B. , Carol Hernan , Gorlick Richard , Kolb E. Anders , Kang Min H. , Reynolds C. Patrick , Kurmasheva Raushan T. , Whiteman Kathleen R. , Smith Malcolm Anders 
Published: June 2012

Abstract
Introduction: Lorvotuzumab mertansine (LM) is a conjugate consisting of the cytotoxic maytansinoid, DM1, covalently linked to the humanized monoclonal antibody lorvotuzumab, which selectively binds to CD56 (NCAM, neural cell adhesion molecule). LM is currently in clinical trials for patients with CD56-positive cancers [e.g., small-cell lung cancer (SCLC), multiple myeloma, and Merkel cell carcinoma]. The activity of LM was evaluated against the in vitro and in vivo panels of the Pediatric Preclinical testing Program (PPTP). Methods: LM and its cytotoxic moiety L-DM1-SMe were tested against the PPTP's in vitro cell line panel at concentrations ranging from 0.01 nM to 0.1 μM using the PPTP's standard 96 hour exposure period. LM was tested against a subset of PPTP solid tumor xenografts at a dose of 15 mg/kg by the intravenous route using a weekly × 3 schedule with a total planned testing and observation period of 6 weeks. Models were selected for testing based on their CD56 expression levels.
Results: The relative IC50 (rIC50) for LM and L-DM1-SMe were 35 nM and 2 nM, respectively. The two agents had very distinctive activity patterns, with LM showing its greatest activity against the neuroblastoma panel, and with L-DM1-SMe showing its highest activity against the ALL panel. L-DM1-SMe showed 79-fold greater potency against the ALL panel (median rIC50 1.1 nM) compared to the neuroblastoma panel (median rIC50 84 nM). By contrast, LM showed 1.7-fold greater potency against the neuroblastoma panel (median rIC50 32 nM) compared to the ALL panel (median rIC50 53 nM). The cell lines of the neuroblastoma panel had NCAM (CD56) expression at or above the median expression level for all PPTP xenografts and cell lines, and these cell lines demonstrated corresponding high levels of sensitivity to LM compared to L-DM1-SMe. The converse was true for the ALL cell lines, which had low NCAM (CD56) expression and low sensitivity to LM compared to L-DM1-SMe.
In vivo, LM induced significant differences in EFS distribution compared to control in 15 of 18 (83%) of the evaluable solid tumor xenografts, including all 7 neuroblastoma xenografts. Objective responses were observed in 6 of 18 (33%) solid tumor xenografts [2 complete responses (CR) and 4 maintained CR (MCR)]. CR/MCR responses were observed for 3 of 7 neuroblastoma xenografts and 2 of 5 rhabdomyosarcoma xenografts. The other MCR observed was for the Wilms tumor xenograft KT-10. Each of the 6 xenografts achieving CR or MCR responses showed homogeneous staining by IHC for NCAM (CD56) with expression levels of 3 or 3+ (excepting NB-1643 which showed 2–3 level homogeneous staining). However, other xenografts also showed 3 or 3+ homogeneous staining but did not show tumor regression in response to LM treatment. Comparison of LM in vivo activity to that previously described for vincristine showed that neuroblastoma xenografts with data for both agents were more responsive to LM than to vincristine.
Conclusions: LM shows target-directed activity in vitro and promising activity in vivo against CD56-expressing childhood cancers. Combination testing with topotecan is planned for the neuroblastoma panel to take advantage of previously reported synergistic interactions for topoisomerase-I inhibitors administered with microtubule-targeting agents (Cancer Chemother Pharmacol 2001:47; 211–21).
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 C105.