Targeting CD56 (NCAM)-Expressing Neoplasms with Lorvotuzumab Mertansine

Abstract

CD56, also known as neural cell adhesion molecule (NCAM), is a type 1 transmembrane glycoprotein that is expressed on neuronal tissue, skeletal and heart muscle, various cells of neuroendocrine origin, as well as natural killer cells and a subset of T cells. The extracellular domain comprises five immunoglobulin-like domains and two fibronectin domains. The molecule is thought to play an important role in cell–cell and cell–matrix interactions, especially in early development. A number of different isoforms can be produced by differential splicing of mRNA, and further heterogeneity is provided by differential glycosylation, including a poly(sialic acid)-containing glycoform. A variety of cancers express CD56, both solid tumors of cell types that express a neuroendocrine phenotype such as small cell lung cancer and hematologic cancers such as multiple myeloma. Lorvotuzumab mertansine is an ADC composed of a humanized IgG1 version of the murine monoclonal anti-CD56 antibody, N901, conjugated to the maytansinoid DM1, a potent tubulin-binding agent, through reaction with a disulfide-containing linker. Lorvotuzumab mertansine displays antitumor activity in a number of in vivo preclinical studies, including xenograft models of small cell lung cancer (SCLC), multiple myeloma, and ovarian cancer. The initial clinical development program for lorvotuzumab mertansine consisted of three completed phase I studies evaluating the compound as monotherapy in advanced SCLC, CD56-positive solid tumors, and CD56-positive multiple myeloma. To date, more than 260 patients have been treated with lorvotuzumab mertansine. In the phase I studies, preliminary signals of single-agent activity, including partial and complete responses, were seen in patients with SCLC, Merkel cell carcinoma, and multiple myeloma. The conjugate is well tolerated, with little or no clinically significant myelosuppression noted at the MTD, conducive to its development in combination with standard-of-care chemotherapy regimens. The ongoing clinical development program comprises two studies evaluating lorvotuzumab mertansine as part of combination regimens with lenalidomide/dexamethasone in CD56-positive multiple myeloma in a single arm study and with carboplatin/etoposide in previously untreated extensive-stage SCLC in a randomized two-arm study.