RT Journal Article SR Electronic T1 Overcoming leukemia heterogeneity by combining T cell engaging bispecific antibodies JF Journal for ImmunoTherapy of Cancer JO J Immunother Cancer FD BMJ Publishing Group Ltd SP e001626 DO 10.1136/jitc-2020-001626 VO 8 IS 2 A1 Sayed Shahabuddin Hoseini A1 Madelyn Espinosa-Cotton A1 Hong-fen Guo A1 Nai-Kong V Cheung YR 2020 UL http://jitc.bmj.com/content/8/2/e001626.abstract AB Background Leukemia represents about 5% of all human cancers. Despite advances in therapeutics, a substantial number of patients succumb to the disease. Several subtypes of leukemia are inherently more resistant to treatment despite intensive chemotherapy or targeted therapy.Methods Here we describe the generation of T cell engaging (CD3) bispecific antibodies (BsAbs) built on humanized IgG frameworks using the IgG(L)-scFv format against two targets expressed on acute lymphoblastic leukemia (ALL) and on acute myeloid leukemia (AML).Results Each BsAb mediated potent anti-leukemia effect against ALL (CD19) and AML (CD33) in vitro and in xenograft models. Importantly, the CD19-specific BsAb (BC250) was effective against hematogenous spread preventing metastases to liver and kidney in mice bearing ALL and Burkitt’s lymphoma xenografts. BC250 was more potent than the The Food and Drug Administration (FDA)-approved BsAb blinatumomab against ALL xenografts in vivo as measured by tumor bioluminescence and mouse survival. Furthermore, the combination of the CD19 and CD33 BsAbs in two xenograft models of mixed phenotype acute leukemia (biphenotypic and bilineal leukemia) was far superior than monotherapy with either of the BsAbs alone.Conclusions Selective combinations of these leukemia-specific BsAb offer the potential to overcome tumor heterogeneity or clonal escape in the modern era of antibody-based T cell-driven immunotherapy.