AML patients cured after allogeneic hematopoietic stem cell transplantation develop antibodies capable of directly killing AML blasts in vitro and in vivo
G. Moiset1,2, M.A. Gillissen1,2, M. Kedde1, G. de Jong1,2, E. Yasuda1, S.E. Levie1, A.Q. Bakker1, Y. B. Claassen1, K. Wagner1, M. Böhne1, M.H.J. van Oers2, D. Speijer3, P.J. Hensbergen4, P.M. van Helden1, T. Beaumont1, H. Spits1, M.D. Hazenberg2
1AIMM Therapeutics, 2Department of Hematology, 3Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands; 4Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) can cure acute myeloid leukemia (AML) when the donor immune system generates a potent graft versus leukemia (GvL) response. While the role of T and NK cells in GvL responses has been established, the contribution of B cells is unresolved. Antibodies against tumor-associated antigens are present in serum of patients with strong GvL responses but their role is unknown.
We selected 5 patients with high-risk AML, 5 years disease-free after allogeneic HSCT, and thus have mounted a potent GvL response. We isolated memory B cells from their blood and identified clonal B cell lines producing antibodies recognizing antigens expressed on the cell surface of AML cells, but not on normal cells. Antibodies were donor-derived, and a number of them recognized the U5 snRNP200 complex, a component of the spliceosome located in the nucleus of normal cells but exposed on the cell membrane of AML cells. Only allogeneic HSCT recipients with AML (4 out of 5), and not multiple myeloma, produced those antibodies. The antibodies induced death of AML cells in the absence of cytotoxic leukocytes or complement in a Fc receptor dependent way. Strikingly, they also induced cell death in a human AML mouse model, resulting in a significant tumor growth inhibition, demonstrating the potency of the humoral immune system in tumor immunology.
This study identified cell surface expressed snRNP200 as a highly specific tumor antigen for AML and antibodies against it may have considerable therapeutic value for AML patients.