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AML-specific cytotoxic antibodies in patients with durable graft versus leukemia responses

Marijn A. Gillissen, Martijn Kedde, Greta de Jong, Gemma Moiset, Etsuko Yasuda, Sophie E. Levie, Arjen Q. Bakker, Yvonne B. Claassen, Koen Wagner, Martino Böhne, Paul J. Hensbergen, Dave Speijer, Pauline M. van Helden, Tim Beaumont, Hergen Spits and Mette D. Hazenberg

Key points

  • High-risk AML patients with lasting graft versus leukemia responses generate antibodies that kill leukemic blasts.

  • The target of these cytotoxic antibodies is the U5 snRNP200 complex that is expressed on the membrane of AML blasts.

Abstract

Most acute myeloid leukemia (AML) patients can only be cured when an allogeneic hematopoietic stem cell transplantation (HSCT) induces a graft versus leukemia immune response (GvL). While the role of T cells and NK cells in tumor immunology has been established, less is known about the contribution of B cells. From B cells of high-risk AML patients with potent and lasting GvL responses we isolated monoclonal antibodies directed against antigens expressed on the cell surface of AML cells but not on normal hematopoietic and non-hematopoietic cells. A number of these donor-derived antibodies recognized the U5 snRNP200 complex, a component of the spliceosome that in normal cells is found in the cell. In AML however, the U5 snRNP200 complex is exposed on the cell membrane of leukemic blasts. U5 snRNP200 complex-specific antibodies induced death of AML cells in a FcR dependent way in the absence of cytotoxic leukocytes or complement. In an AML mouse model, treatment with U5 snRNP200 complex-specific antibodies led to significant tumor growth inhibition. Thus, donor derived U5 snRNP200 complex-recognizing AML-specific antibodies may contribute to anti-tumor responses.

  • Submitted February 14, 2017.
  • Accepted September 30, 2017.