AT1413: an antibody isolated from a cured Acute Myeloid Leukemia patient that is highly efficacious against AML in vivo
G. de Jong1,2, M.A. Gillissen1,2, M. Kedde1, E. Yasuda1, S.E. Levie1, K. Wagner1, A.Q. Bakker1, M.J. Kersten2, P.J. Hensbergen3, T. Beaumont1, P.M. van Helden1, H. Spits1, M.D. Hazenberg2
1AIMM Therapeutics, 2AMC Amsterdam, 3UMC Leiden; The Netherlands
Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are high-risk diseases with a poor prognosis. Immunotherapy for those diseases is hampered by the lack of tumor-specific targets. To identify AML-specific epitopes that could serve as novel targets for immunotherapy, we searched the B cell repertoire of a patient with a lasting and potent graft versus AML response after allogeneic hematopoietic stem cell transplantation for AML-specific antibodies.
We identified a donor-derived B cell clone that produced an IgG1 antibody, AT1413, that specifically interacted with AML cell lines and with the patient’s own AML blasts. AT1413 showed a low level of activity with normal myeloid cells but not with lymphoid cells. The variable regions of AT1413 antibody contained a high number of somatic hypermutations indicating antigen experience.
Biochemical analysis revealed that AT1413 recognizes a unique sialylated epitope on CD43 (CD43s). CD43s is overexpressed on all types of AML and MDS, as illustrated by its reactivity with freshly isolated blasts of each of 60 randomly selected AML and MDS patients in our clinic.
AT1413 induced ADCC and CDC of target cells in vitro. AT1413 is highly efficacious against AML cells in vivo. We inoculated human immune system mice with AML cells iv. After tumor engraftment mice were dosed biweekly with AT1413. We observed strongly reduced numbers of AML cells in all organs including bone marrow in AT1413 but not in control mice. Importantly, AT1413 treatment did not affect numbers of non-malignant human myeloid cells.
In conclusion, we have identified an antibody which recognizes a unique sialylated epitope on CD43, which is selectively over-expressed on AML and MDS blasts. This antibody was able to eliminate AML cells in vivo and therefore has high therapeutic potential.
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