A CD19/CD3 bispecific antibody for effective immunotherapy of chronic lymphocytic leukemia in the ibrutinib era
| Autor: | Eman L. Dadashian, Nakhle S. Saba, Sivasubramanian Baskar, Erika M. Cook, Hannah R. Robinson, Junpeng Qi, Christoph Rader, Adrian Wiestner, Inhye E. Ahn, Keyvan Keyvanfar, Chingiz Underbayev, Clare Sun, Sarah E. M. Herman, Cydney M. Nichols |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
CD3 Complex Chronic lymphocytic leukemia medicine.medical_treatment Mice SCID Biochemistry Mice chemistry.chemical_compound 0302 clinical medicine Piperidines Mice Inbred NOD immune system diseases hemic and lymphatic diseases Antibodies Bispecific Tumor Cells Cultured Lymphoid Neoplasia biology Hematology Leukemia surgical procedures operative 030220 oncology & carcinogenesis Ibrutinib Blinatumomab Immunotherapy BLOOD Commentary medicine.drug Antigens CD19 Immunology Context (language use) chemical and pharmacologic phenomena CD19 03 medical and health sciences medicine Animals Bruton's tyrosine kinase Humans Salvage Therapy business.industry Adenine Cell Biology medicine.disease Xenograft Model Antitumor Assays Leukemia Lymphocytic Chronic B-Cell 030104 developmental biology Pyrimidines chemistry Drug Resistance Neoplasm biology.protein Cancer research Pyrazoles business Single-Chain Antibodies |
| Popis: | 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-naive 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-naive 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-naive 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 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. |
| Databáze: | OpenAIRE |
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