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To enhance antitumor efficacy and overcome potential immune escape, we developed a novel approach to design a CD19\/CD22\/CD3 trispecific antibody (tsAb) by site-specifically fusing anti-CD19 scFv (FMC63) and anti-CD22 nanobody (Nb25) to the defined sites of the CD3 antigen-binding fragment (Fab, SP34). This strategy allows for the optimal formation of immune synapses mediated by CD19\/CD22\/CD3 between target cells and T cells. Optimized tsAb can be superior for inducing T-cell\u2212specific cytotoxicity and cytokine production against CD19+ and\/or CD22+ tumor cells compared to other tsAb formats, and demonstrated significantly enhanced antitumor efficacy and the ability to overcome immune escape compared with the corresponding bsAbs alone or in combination, as well as with blinatumomab. In addition, tsAb treatment can lead to the long-term elimination of primary B-ALL patient samples in the PDX model and significantly prolong survival. This novel approach provides unique insight into the structural optimization of T-cell\u2212redirected multispecific antibodies using site-specific recombination, and may be broadly applicable to heterogeneous and resistant tumor populations as well as solid tumors.<\/jats:p>","DOI":"10.1182\/blood.2022016243","type":"journal-article","created":{"date-parts":[[2022,8,18]],"date-time":"2022-08-18T18:02:52Z","timestamp":1660845772000},"page":"1790-1802","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":76,"title":["A novel CD19\/CD22\/CD3 trispecific antibody enhances therapeutic efficacy and overcomes immune escape against B-ALL"],"prefix":"10.1182","volume":"140","author":[{"given":"Lijun","family":"Zhao","sequence":"first","affiliation":[{"name":"1State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, 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