In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 1785-1785
Abstract:
Acute myeloid leukemia (AML) is characterized by the accumulation of abnormal blast cells in the bone marrow and blood. While high intensity chemotherapy and allogeneic stem cell transplantation cure a subset of patients with AML, many patients are ineligible or do not respond sufficiently to these therapies. One potential reason for treatment failure in a particular patient may be the inability to reach and eliminate residual leukemic stem cells (LSCs) located in the bone marrow. T-cell mediated cytotoxicity, targeting LSCs with high expression of certain leukemic antigens, represents an attractive therapeutic strategy for relapsed and refractory AML. In this study, the proprietary Cross-Over-Dual-Variable-Domain (CODV) format was applied to a fully humanized IgG1 backbone with reduced Fc functionality, resulting in a bispecific T-cell engager (TCE), CD123-CODV-TCE, that binds to both CD3 on T cells and CD123 (α-chain of the interleukin-3 receptor) on AML blasts and LSCs. CD123-CODV-TCE displayed high affinity for human CD123 and medium affinity for human CD3 proteins. As expected, CD123-CODV-TCE activated CD4-positive and CD8-positive T cells only in the presence of cells expressing the CD123 target, such as THP1 (an AML tumor cell line), and induced killing of these cells with an EC50 in a picomolar range. Potential cytotoxic activity of CD123-CODV-TCE was also evaluated on CD123-expressing normal blood cells such as plasmacytoid dendritic cells (pDC) and monocytes. CD123-CODV-TCE was shown to deplete pDC and monocyte from human Healthy Donor (HD) Peripheral Blood Mononuclear Cells (PBMC) with an EC50 in the picomolar range. This efficacy correlated with the release of numerous cytokines, thus highlighting the potential risk of cytokine release syndrome as described for other TCE's. In an in vivo disseminated AML model using CD123+ Molm13-luc human AML cell line, treatment of the mice with CD123-CODV-TCE suppressed AML tumor growth in the bone marrow compartment following co-injection of primary human T cells. In this murine pre-clinical model, CD123-CODV-TCE displayed favorable pharmacokinetic properties with a terminal half-life of 3 days. To investigate CD123-CODV-TCE activity on myeloid blast cells and LSC, in vivo efficacy studies were performed in NSG mice injected with primary human AML cells obtained from patients. In this model, CD123-CODV-TCE induced the killing of primary AML cells by activating human autologous T cells. Taken together, these results indicate that CD123-CODV-TCE can potently and specifically kill CD123+ leukemic cancer cells in vitro and in vivo. CD123-CODV-TCE therefore represents a potential candidate for future clinical development in relapsed and refractory AML. Citation Format: Helene Bonnevaux, Stephane Guerif, Jana Albrecht, Erwan Jouannot, Laurent Bassinet, Agnès Vergezac, Christian Beil, Christian Lange, Wulf Dirk Leuschner, Anne Caron, Celine Amara, Cedric Barriere, Justine Siavellis, Valerie Bardet, Ernesto Luna, Donald Drake, Ercole Rao, Corina Oprea, Peter Wonerow, Chantal Carrez, Veronique Blanc, Karl Hsu, Dmitri Wiederschain, Paula G. Fraenkel. Pre-clinical development of a novel CD3-CD123 bispecific T-cell engager using Cross-Over-Dual-Variable-Domain (CODV) format for the treatment of acute myeloid leukemia (AML) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1785.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2018-1785
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2018
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
