AI Article Synopsis

  • Ibrutinib, a Bruton tyrosine kinase inhibitor, effectively treats chronic lymphocytic leukemia (CLL) but necessitates additional therapies to enhance patient responses and tackle drug resistance.* -
  • Researchers developed an innovative bispecific antibody, CD19/CD3-scFv-Fc, which has a longer half-life of approximately 5 days and showed over 90% CLL cell kill rate in lab settings, significantly outperforming blinatumomab, which requires continuous dosing.* -
  • CD19/CD3-scFv-Fc not only killed more CLL cells in ibrutinib-treated patients but also exhibited strong activity against CLL cells with acquired resistance, suggesting its potential as a complementary

Article Abstract

The Bruton 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 (bispecific T-cell engager) format, is approved by the US Food and Drug Administration for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Because of 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 ∼5 days. In in vitro experiments, both CD19/CD3-scFv-Fc and blinatumomab induced >90% killing of CLL cells from treatment-naïve patients. Antileukemic 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 and/or mutations in vitro and in vivo using patient-derived xenograft models. Taken together, these data support investigation of CD19/CD3 bsAb's and other T cell-recruiting bsAb's as immunotherapies for CLL, especially in combination with ibrutinib or as rescue therapy in ibrutinib-resistant disease.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6073325PMC
http://dx.doi.org/10.1182/blood-2018-02-830992DOI Listing

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