A CD19/CD3 bispecific antibody for effective immunotherapy of chronic lymphocytic leukemia in the ibrutinib era
Open accessAbstract
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…
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A novel CD19/CD3 bispecific antibody has shown in vitro and in vivo (patient-derived xenograft) activity against CLL by recruiting autologous T cells to form cytolytic synapses with CD19+ CLL cells.
“Preclinical work with anovel CD19/CD3 bsAbhas shown in vitro and in vivo(patient-derived xenograft) activity against CLL by recruiting autologous Tcells to form cytolytic synapses with the CD19+ CLL cells (94).”
From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [94]
T cells from patients on ibrutinib, when treated with CD19/CD3 bispecific antibody in vitro, mounted faster cytotoxic responses than T cells from ibrutinib-naïve patients.
“Tcells obtained from patients on ibrutinib andtreated with CD19/CD3 bsAbin vitromounted faster cytotoxic responses than Tcells from ibrutinib-naïve patients (94).”
From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [94]
Bispecific antibodies represent a promising therapeutic strategy for relapsed/refractory CLL and a potential combination partner to deepen responses in patients on targeted therapy, especially with BTK inhibitors and venetoclax.
“Overall, bsAb represent a promising therapeutic strategy for relapsed/refractory CLL, and as a potential combination partner to deepen responses in patients on targeted therapy, especially in conjunction with BTKi and venetoclax (94, 95, 98).”
From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [94]
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Resistance Mechanisms for the Bruton's Tyrosine Kinase Inhibitor Ibrutinib
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Mhibik, M., Gaglione, E. M., Eik, D., Herrick, J., Le, J., Ahn, I. E., Chiu, C., Wielgos-Bonvallet, M., Hiemstra, I. H., Breij, E. C. W., et al. (2023) · Blood Advances · doi:10.1182/bloodadvances.2022009517 · Cited by 43 · see citing works
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Self-citationResistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy
Gruessner, C., Wiestner, A., & Sun, C. (2025) · Leukemia & Lymphoma · doi:10.1080/10428194.2025.2466101 · Cited by 6 · see citing works
“…and in vivo (patient-derived xenograft) activity against cll by recruiting autologous t cells to form cytolytic synapses with the cD19+ cll cells [93]. t cells obtained from patients on ibrutinib and treated with cD19/cD3 bsAb in vitro mounted faster cytotoxic responses than t cells from…”
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- Authors
- Robinson, H. R., Qi, J., Cook, E. M., Nichols, C., Dadashian, E. L., Underbayev, C., Herman, S. E. M., Saba, N. S., Keyvanfar, K., Sun, C., Ahn, I. E., Baskar, S., Rader, C., & Wiestner, A.
- Affiliations
- National Institutes of Health (US)
- Scripps Research Institute (US)
- Tulane University (US)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2018-08-02
- Volume
- 132
- Issue
- 5
- Pages
- 521-532
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC6073325
- OpenAlex
- W2800173328
- Cited by
- 108
- References
- 4
- Citations by year
- 2026: 1 · 2025: 13 · 2024: 14 · 2023: 15 · 2022: 15 · 2021: 19 · 2020: 18 · 2019: 11 · 2018: 2
- FWCI
- 7.07
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Blood (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Pharmacyclics
- National Heart, Lung, and Blood Institute
- National Cancer Institute (R01CA181258)
- Topics
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Keywords
- chronic lymphocytic leukemia, ibrutinib, ibrutinib resistance, T cell recruitment, B-cell depletion, patient-derived xenografts, combination immunotherapy, salvage therapy
- MeSH terms
- Adenine, Animals, Humans, Piperidines, Pyrazoles, Pyrimidines, Tumor Cells, Cultured, Leukemia, Lymphocytic, Chronic, B-Cell, Mice, SCID, Mice, Inbred NOD, Salvage Therapy, CD3 Complex, Antibodies, Bispecific, Antigens, CD19, Drug Resistance, Neoplasm, Xenograft Model Antitumor Assays, Mice, Single-Chain Antibodies
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