Immunotherapeutic Targeting of Mesothelin in Acute Myeloid Leukemia in Vitro with Anetumab Ravtansine and a Novel Antibody-Drug Conjugate

Acute myeloid leukemia (AML) is a high-risk malignancy with overall poor outcomes across the age spectrum. Attempts to intensify cytotoxic chemotherapeutic regimens in recent decades have been limited by toxic acute and late effects, establishing the necessity of targeted therapy development. Immunotherapy is a highly promising treatment strategy in AML; however, its development has been limited as agents with potent anti-leukemic activity often confer significant hematopoietic toxicities. We previously reported the identification of an ideal potential immunotherapeutic target, mesothelin (MSLN), a cell surface protein expressed in 37% of childhood and young adult AML as well as older adult AML that, importantly, is absent in normal hematopoietic cells. Mesothelin is overexpressed in a number of solid tumors and has been studied as a target in solid tumors with various immunotherapeutic agents, including the antibody-drug conjugate (ADC) anetumab ravtansine (AR), comprised of an anti-MSLN antibody conjugated to the maytansinoid tubulin inhibitor DM4. We evaluated AR as well as a novel MSLN-targeted ADC for their ability to induce MSLN-directed cytotoxicity in several cell lines engineered to express MSLN.As we have previously reported, the leukemia cell line K562 transduced to overexpress MSLN (K562+MSLN) was highly sensitive to AR in vitro with an IC50 of 1.4 nM (Fig. 1a). Furthermore, AR was highly active in vivo in K562+MSLN xenograft-bearing mice. We sought to extend the ...
Source: Blood - Category: Hematology Authors: Tags: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Poster I Source Type: research