Tumor Specific Glycosylated CD43 Is a Novel and Highly Specific Target for Acute Myeloid Leukemia and Myelodysplastic Syndrome
Authors: Gillissen Marijn A. , Kedde Martijn , de Jong Greta , Yasuda Etsuko , Levie Sophie E. , Bakker Arjen Q. , Kersten Marie Jose , Hensbergen Paul , Beaumont Tim , van Helden Pauline M. , Spits Hergen , Hazenberg Mette D. 
Published: October 2019

Background: Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are high-risk diseases with a poor prognosis. Even with intensive treatment regimens less than 50% of patients can be cured, and for the majority of patients - those over 65 years of age and/or patients with comorbidities - such intensive regimens are not feasible. Novel therapeutic approaches such as immunotherapy directed against a specific tumor target are highly needed.

Aims: The aim of our study was to identify antibodies that are highly specific for AML and to discover novel tumor-specific antigens, widely expressed on AML and MDS but not on healthy hematopoietic and non-hematopoietic cells.

Methods: Allogeneic bone marrow transplantation is an immunotherapy with proven therapeutic efficacy. We selected a patient with high-risk AML who remained disease free, now more than 5 years after receiving an allogeneic HSCT and therefore can be considered to have mounted a potent graft versus leukemia response. To study the antibody repertoire of this patient we isolated CD27+ IgG+ memory B lymphocytes, about 2 years after the transplant. These cells were transduced with Bcl-6 and Bcl-xL to generate plasmablast B cell clones that produce antibodies and express the B cell receptor on the cell surface. Supernatants of these B cell clones were used to screen for binding to surface antigens on the AML cell line THP-1.

Results: We identified an donor derived IgG1 antibody, AT1413, that specifically bound to AML cell lines THP-1, MOLM-13, SH-2 and others, but not to normal bone marrow cells or non-hematopoietic cells. The antibody also interacted with AML blasts from the allogeneic HSCT patient from whom the antibody was derived, and with leukemic blasts isolated from newly diagnosed AML and MDS patients. Biochemical analysis revealed that AT1413 recognizes a sialylated epitope on CD43 which is specifically expressed on all types of AML and MDS cells, as illustrated by its reactivity with blasts of each of 60 randomly selected AML and MDS patients in our clinic. Since the target it is also expressed by CD34+ hematopoietic progenitor cells obtained from fetal liver and fetal bone marrow, but not by post-natal hematopoietic progenitor cells, it can be considered to be a oncofetal epitope. AT1413 induced antibody-dependent cell-mediated cytotoxicity and complement dependent cytotoxicity of AML cell lines and primary blasts.

Summary and conclusion: We have identified oncofetal-sialylated CD43 (CD43os) as a novel tumor-specific target that is widely expressed on AML and MDS blasts. Antibodies against this target have therefore high potential as therapeutic antibodies, either as a naked antibody or manufactured into an antibody-drug conjugate, bispecific T cell engager or CAR (chimeric antigen receptor) T cell.

Disclosures

Kersten: Celgene: Research Funding; Amgen: Honoraria.