A Novel Bispecific T-Cell Engager (CD1a x CD3") BTCE Is Effective against Cortical-Derived T Cell Acute Lymphoblastic Leukemia (T-ALL) Cells

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy burdened bypoor prognosis. While huge progress of immunotherapy has recently improved the outcome ofB-cell malignancies, the lack of tumor-restricted T-cell antigens still hampers its progress in T-ALL.Therefore, innovative immunotherapeutic agents are eagerly awaited. To this end, we generated anovel asymmetric (2 + 1) bispecific T-cell engager (BTCE) targeting CD1a and CD3" (CD1a x CD3")starting from the development of a novel mAb named UMG2. UMG2 mAb reacts against CD1a, aglycoprotein highly expressed by cortical T-ALL cells. Importantly, no UMG2 binding was found on normal T-cells. CD1a x CD3" induced high T-cell mediated cytotoxicity against CD1a+ T-ALLcells in vitro, as demonstrated by the concentration-dependent increase of T-cell proliferation,degranulation, induction of cell surface activation markers, and secretion of pro-inflammatorycytokines. Most importantly, in a PBMC-reconstituted NGS mouse model bearing human TALL,CD1a x CD3" significantly inhibited the growth of human T-ALL xenografts, translatinginto a significant survival advantage of treated animals. In conclusion, CD1a x CD3" is a novelBTCE highly active against CD1a-expressing cortical-derived T-ALL cells suitable for clinicaldevelopment as an effective therapeutic option for this rare and aggressive disease.