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A CD19/CD3 bispecific antibody for effective immunotherapy of chronic lymphocytic leukemia in the ibrutinib era

Hannah R. Robinson, Junpeng Qi, Erika M. Cook, Cydney Nichols, Eman L. Dadashian, Chingiz Underbayev, Sarah E.M. Herman, Nakhle S. Saba, Keyvan Keyvanfar, Clare Sun, Inhye E. Ahn, Sivasubramanian Baskar, Christoph Rader and Adrian Wiestner

Key points

  • A CD19/CD3 single chain Fv-Fc bispecific antibody mediated potent killing of CLL cells by autologous T cells in vitro and in vivo.

  • Bispecific antibody-mediated cytotoxicity was enhanced by prior therapy with ibrutinib and extended to ibrutinib-resistant disease.

Abstract

The Bruton's tyrosine kinase inhibitor ibrutinib induces high rates of clinical response in chronic lymphocytic leukemia (CLL). However, there remains a need for adjunct treatments to deepen response and to overcome drug resistance. Blinatumomab, a CD19/CD3 bispecific antibody (bsAb) designed in the BiTE® format, is FDA approved for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Due to its short half-life of 2.1 hours, blinatumomab requires continuous intravenous dosing for efficacy. We developed a novel CD19/CD3 bsAb in the single-chain Fv-Fc format (CD19/CD3-scFv-Fc) with a half-life of approximately 5 days. In in vitro experiments, both CD19/CD3-scFv-Fc and blinatumomab induced >90% killing of CLL cells from treatment-naïve patients. Anti-leukemic activity was associated with increased autologous CD8 and CD4 T cell proliferation, activation, and granzyme B expression. In the NOD/SCID/IL2Rγnull patient-derived xenograft mouse model, once-weekly treatment with CD19/CD3-scFv-Fc eliminated >98% of treatment-naïve CLL cells in blood and spleen. By contrast, blinatumomab failed to induce a response, even when administered daily. We next explored the activity of CD19/CD3-scFv-Fc in the context of ibrutinib treatment and ibrutinib resistance. CD19/CD3-scFv-Fc induced more rapid killing of CLL cells from ibrutinib-treated patients than those from treatment-naïve patients. CD19/CD3-scFv-Fc also demonstrated potent activity against CLL cells from patients with acquired ibrutinib-resistance harboring BTK and/or PLCG2 mutations in vitro and in vivo using patient-derived xenograft models. Taken together, these data support investigation of CD19/CD3 bsAbs and other T cell-recruiting bsAbs as immunotherapies for CLL, especially in combination with ibrutinib or as rescue therapy in ibrutinib-resistant disease.

  • Submitted February 5, 2018.
  • Accepted April 29, 2018.