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Engineered bispecific antibodies that recruit cytotoxic lymphocytes to kill specific tumor cells have been showing promising clinical results. Here, we describe a bispecific single-chain Fv (scFv) immunofusion or BIf to target CD123(+) leukemia, that contains an anti-CD123 scFv fused at the N-terminus of human IgG1 hinge-C(H)2-C(H)3, and an anti-CD3 scFv fused at C-terminus. When expressed from transfected CHO-S cells, CD123xCD3 BIf forms a homodimer that provides a structure of N-terminal tumor-targeting domain that closely resembles natural antibody. The CD123xCD3 dimeric structure also provides binding affinity to CD123(+) tumor cells with a Kd of 10(-10) M, one to two orders of magnitude stronger than traditional bispecific antibody constructs. The location of the anti-CD3 scFv at C-terminus of BIf reduces the binding affinity to CD3(+) T cells by two orders, which could help to prevent non-specific T-cell activation. CD123xCD3 BIf is able to achieve T-cell-mediated target cell killing activities at low pM levels with E/T ratios as low as 2. Overall, the inclusion of human IgG1 constant region in BIf construct increases target cell-binding affinity; potentially increases serum half-life by its larger size and FcRn-mediated salvage system; and includes the abilities to activate the additional antibody-mediated cellular cytotoxicities.

Engineering a CD123xCD3 bispecific scFv immunofusion for the treatment of leukemia and elimination of leukemia stem cells