In vivo expression of anti-CD19/CD3 BiTE by liver-targeted AAV for the treatment of B cell malignancies

Abstract

Abstract Anti-CD19/CD3 bispecific T-cell engagers (CD19BiTE) has shown promising efficacy in patients with relapsed or refractory (r/r) B-cell malignancies. However, the short half-life of CD19BiTE necessitates long-term repeated administration with rest period, which not only increases the costs but also compromises the efficacy. Long-term and stable expression of CD19BiTE is crucial for achieving durable responses of B-cell malignancies. Adeno-associated virus (AAV)-mediated gene therapy has been demonstrated to achieve long-term efficacy for multiple diseases. Here, we generated liver-targeted AAV encoding CD19BiTE (AAV-CD19BiTE) and achieved sustained expression of CD19BiTE for more than six months. The results indicated that AAV-CD19BiTE could significantly reduce the tumor burdens in CD19+ B-cell malignancies xenograft model via a single injection of AAV-CD19BiTE. Meanwhile, more CD3+, CD4+, CD8+T, and activated CD8+T cells were observed in lymphoma microenvironment after therapy with AAV-CD19BiTE. In addition, AAV-CD19BiTE was also proved to have a strong antitumor activity in patient-derived xenograft (PDX) model of B-cell lymphoma. Altogether, in vivo expression of CD19BiTE circumvents the problem of short half-life and may hold promise as a new therapeutical strategy for CD19+ B-cell malignancies via a single injection of AAV.