Robinson et al. developed a CD19/CD3 bispecific antibody in the single-chain Fv-Fc format with a half-life of approximately 5 days. In human ex vivo and murine xenograft in vivo models of chronic lymphocytic leukemia (CLL), the antibody induced autologous T cell expansion, activation, and granzyme B expression, and led to robust CLL cell killing in blood and spleen. The antibody was effective with PBMCs from treatment-naive and ibrutinib-treated patients, and induced a faster response in the latter case, suggesting synergy with ibrutinib. Response was also observed against CLL cells from patients who were ibrutinib-resistant.
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(R) 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-naive patients. Anti-leukemic activity was associated with increased autologous CD8 and CD4 T cell proliferation, activation, and granzyme B expression. In the NOD/SCID/IL2Rgammanull 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 bsAbs and other T cell-recruiting bsAbs as immunotherapies for CLL, especially in combination with ibrutinib or as rescue therapy in ibrutinib-resistant disease.
Author Info: (1) Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States. (2) Department of Immunology and Microbiology, The Scr
Author Info: (1) Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States. (2) Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, United States. (3) Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States. (4) Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States. (5) Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States. (6) Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States. (7) Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States. (8) Section of Hematology and Medical Oncology, Department of Medicine, Tulane University, New Orleans, LA, United States. (9) Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States. (10) Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States. (11) Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States. (12) Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States. (13) Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, United States. (14) Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States; wiestnera@mail.nih.gov.
