Abstract 1783: UMG1, a novel humanized monoclonal antibody against a glysosylated-CD43-related epitope, induces antibody-dependent cellular cytotoxicity (ADCC) on human T-cell acute lymphoblastic leukemia cells
Authors: Cirino Botta, Maria E. Gallo Cantafio, Chiara Buracchi, Maria A. Siciliano, Maria Cucè, Caterina Riillo, Franca M. Tuccillo, Daniele Caracciolo, Emanuela Altomare, Mariamena Arbitrio, Maria T. Di Martino, Marco Rossi, Andrea Biondi, Giuseppe Gaipa, Pierosandro Tagliaferri, Pierfrancesco Tassone
Journal: Cancer Research (2018)

Abstract T-cell acute lymphoblastic leukemia (T-ALL) is a hematologic malignancy accounting for about 25% of all acute leukemias. Due to the poor therapeutic scenario and severe prognosis of T-ALL, novel drugs are eagerly awaited. The targeting of tumor-associated antigens by monoclonal antibodies (mAb) for induction of immune-mediated cellular cytotoxicity is presently a promising immunotherapeutic strategy. We previously developed a novel mAb direct against a heavy glycosylated oncofetal epitope of CD43 (UN1) with known potential application as therapeutic and diagnostic tool. By screening different cancer cell lines, we observed that UN1 is highly and selectively expressed on malignant T-ALL cells. The expression of UN1 was then evaluated in 38 T-ALL patient-derived blasts and high correlation for a specific subset of patients (about 80%) belonging to the cortical T-ALL group (EGIL T3) was detected. Accordingly, we developed a humanized mAb, (UMG1) and an afucosylated enginereed version (a-UMG1). Therefore, to elucidate the mechanism of action of these mAbs, we investigated complement-mediated cytotoxicity (CDC), ADCC and antibody-dependent cellular phagocytosis (ADCP). To this aim, T-ALL cells (HPB-ALL and CCRF-CEM) have been cultured in the presence of complement, peripheral blood mononuclear cells (PBMCs), NK-92-CD16+ cells or macrophages, using increasing concentrations of both mAbs. Notably, we observed that mAbs treatment alone did not exert either cellular cytotoxicity or CDC on target cells. Conversely, both mAbs induced significant ADCC mediated by PBMCs and NK-92-CD16+ cell line in term of NK degranulation and cytotoxicity and macrophage-mediated ADCP. In vivo results demonstrated a powerful activity of UMG1 in 3 different models of T-ALL in NSG mice in the presence or absence of NK-92-CD16+ cells. Specifically, in two subcutaneous models, we observed a strong ability of both mAbs to delay tumor growth and increase survival of treated mice. As expected, the combinatory treatment with NK-92-CD16+ cell line strongly improved the activity of a-UMG1. Importantly, in the orthotopic disseminated model, which better reproduces the human T-ALL disease, we observed 5 out of 20 treated mice alive and free of disease 100 days after injection. Furthermore, to explore the possibility of combination therapy, the modulation of UN1 expression by chemotherapeutic agents in T-ALL was investigated. Interestingly, we observed that methotrexate and doxorubicin , alone or in combination, increased UN1 expression at low nanomolar concentrations, and improved ADCC in vitro. In conclusion, we demonstrated that UMG1 and a-UMG1 represent a novel promising immune-therapeutic tool for the treatment of T-ALL patients. Citation Format: Cirino Botta, Maria E. Gallo Cantafio, Chiara Buracchi, Maria A. Siciliano, Maria Cucè, Caterina Riillo, Franca M. Tuccillo, Daniele Caracciolo, Emanuela Altomare, Mariamena Arbitrio, Maria T. Di Martino, Marco Rossi, Andrea Biondi, Giuseppe Gaipa, Pierosandro Tagliaferri, Pierfrancesco Tassone. UMG1, a novel humanized monoclonal antibody against a glysosylated-CD43-related epitope, induces antibody-dependent cellular cytotoxicity (ADCC) on human T-cell acute lymphoblastic leukemia cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1783.