作者: van Helden, P M ; de Jong, G ; van der Burg, S H ; Schotte, R ; Verdegaal, E M E ; Claassen, Y B ; van de Berg, D ; Yasuda, E ; Gillissen, M A ; Wagner, K ; Hazenberg, M D ; Levie, S E ; van Hal-van Veen, S E ; Spits, H ; Bartels, L ; Bakker, A Q ; Villaudy, J ; Cercel, M G ; Kedde, M ; Fatmawati, C

Targeted cancer therapy with monoclonal antibodies has proven successful for different cancer types but is limited by the availability of suitable antibody targets. CD43s, a unique sialylated form of CD43 expressed by hematologic malignancies, is a recently identified target and antibodies interacting with CD43s may have therapeutic potential against acute myeloid leukemia (AML) and myelodysplastic syndrome. CD43s is recognized by the human antibody AT1413, that was derived from a high-risk AML patient who successfully cleared leukemia after allogeneic stem cell transplantation. Here we observed that AT1413 binds also to certain non-hematopoietic tumor cells, particularly melanoma and breast cancer. AT1413 immune precipitated CD43s from melanoma cells confirming that it recognizes the same target on melanoma as on AML. AT1413 induced antibody-dependent cellular cytotoxicity against short-term cultured patient-derived melanoma samples. However, AT1413 was unable to affect the growth of melanoma cells in vivo. To increase the efficacy of AT1413 as a therapeutic antibody, we generated two different formats of bispecific T-cell engaging antibodies (TCEs): one binding bivalently (bTCE) and the other monovalently (knob-in-hole; KiH) to both CD43s and CD3ε. In vitro, these TCEs redirected T-cell cytotoxicity against melanoma cells with differences in potencies. To investigate their effects in vivo, we grafted mice that harbor a human immune system with the melanoma cell line A375. Treatment with both AT1413 bTCE and AT1413 KiH significantly reduced tumor outgrowth in these mice. These data indicate a broad therapeutic potential of AT1413 that includes AML and CD43s-expressing solid tumors that originate from CD43-negative tissues.

2019-07-01·Cancer Research1区 · 医学

A Chemo-enzymatically Linked Bispecific Antibody Retargets T Cells to a Sialylated Epitope on CD43 in Acute Myeloid Leukemia

1区 · 医学

Article

作者: Yasuda, Etsuko ; Cercel, Madalina G. ; Bru, Camille ; Hazenberg, Mette D. ; Moiset, Gemma ; van Hal-van Veen, Susan E. ; Bakker, Arjen Q. ; Villaudy, Julien ; Gillissen, Marijn A. ; Kattler, Veronika ; Bartels, Lina ; Wagner, Koen ; de Jong, Greta ; Spits, Hergen ; van Helden, Pauline M. ; Fatmawati, Christien

AbstractAcute myeloid leukemia (AML) is a high-risk disease with a poor prognosis, particularly in elderly patients. Because current AML treatment relies primarily on untargeted therapies with severe side effects that limit patient eligibility, identification of novel therapeutic AML targets is highly desired. We recently described AT1413, an antibody produced by donor B cells of a patient with AML cured after allogeneic hematopoietic stem cell transplantation. AT1413 binds CD43s, a unique sialylated epitope on CD43, which is weakly expressed on normal myeloid cells and overexpressed on AML cells. Because of its selectivity for AML cells, we considered CD43s as a target for a bispecific T-cell–engaging antibody (bTCE) and generated a bTCE by coupling AT1413 to two T-cell–targeting fragments using chemo-enzymatic linkage. In vitro, AT1413 bTCE efficiently induced T-cell–mediated cytotoxicity toward different AML cell lines and patient-derived AML blasts, whereas endothelial cells with low binding capacity for AT1413 remained unaffected. In the presence of AML cells, AT1413 bTCE induced upregulation of T-cell activation markers, cytokine release, and T-cell proliferation. AT1413 bTCE was also effective in vivo. Mice either coinjected with human peripheral blood mononuclear cells or engrafted with human hematopoietic stem cells [human immune system (HIS) mice] were inoculated with an AML cell line or patient-derived primary AML blasts. AT1413 bTCE treatment strongly inhibited tumor growth and, in HIS mice, had minimal effects on normal human hematopoietic cells. Taken together, our results indicate that CD43s is a promising target for T-cell–engaging antibodies and that AT1413 holds therapeutic potential in a bTCE-format.Significance:These findings offer preclinical evidence for the therapeutic potential of a bTCE antibody that targets a sialylated epitope on CD43 in AML.

2017-08-22·Blood Advances2区 · 医学

Patient-derived antibody recognizes a unique CD43 epitope expressed on all AML and has antileukemia activity in mice

2区 · 医学

Article

作者: Yasuda, Etsuko ; Spits, Hergen ; Gillissen, Marijn A. ; Hazenberg, Mette D. ; Kedde, Martijn ; Levie, Sophie E. ; Villaudy, Jullien ; van Helden, Pauline M. ; Bakker, Arjen Q. ; Hensbergen, Paul J. ; Moiset, Gemma ; de Jong, Greta ; Wagner, Koen

Key PointsAT1413 is a monoclonal antibody isolated from a cured patient with AML that recognizes CD43s, a novel epitope expressed by AML and MDS blasts. AT1413 eliminates CD43s-expressing leukemic blasts in vitro and in vivo and may have potential as a therapeutic antibody.

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适应症	最高研发状态	国家/地区	公司	日期
乳腺癌	临床前	-	AIMM Therapeutics BV	2020-06-01
骨髓增生异常综合征	临床前	荷兰	AIMM Therapeutics BV	2019-06-11
急性髓性白血病	临床前	荷兰	AIMM Therapeutics BV	-
黑色素瘤	临床前	荷兰	AIMM Therapeutics BV	-