Cytotoxicity of the CD3×CD20 bispecific antibody epcoritamab in CLL is increased by concurrent BTK or BCL-2 targeting
Open accessAbstract
Chronic lymphocytic leukemia (CLL) is an immunosuppressive disease characterized by increased infectious morbidity and inferior antitumor activity of immunotherapies. Targeted therapy with Bruton's tyrosine kinase inhibitors (BTKis) or the Bcl-2 inhibitor venetoclax has profoundly improved treatment outcomes in CLL. To overcome or prevent drug resistance and extend the duration of response after a time-limited therapy, combination regimens are tested. Anti-CD20 antibodies that recruit cell- and complement-mediated effector functions are commonly used. Epcoritamab (GEN3013), an anti–CD3×CD20 bispecific antibody that recruits T-cell effector functions, has demonstrated potent clinical activity in patients with relapsed CD20+ B-cell non-Hodgkin lymphoma. Development of CLL therapy is ongoing. To characterize epcoritamab-mediated cytotoxicity against primary CLL cells, peripheral blood mononuclear cells from treatment-naive and BTKi-treated patients, including patients progressing on therapy, were cultured with epcoritamab alone or in combination with venetoclax. Ongoing treatment with BTKi and high effector-to-target ratios were associated with superior in vitro cytotoxicity. Cytotoxic activity was independent of CD20 expression on CLL cells and observed in samples from patients whose condition progressed while receiving BTKi. Epcoritamab induced significant T-cell expansion, activation, and differentiation into Th1 and effector memory cells in all patient samples. In patient-derived xenografts, epcoritamab reduced the blood and spleen disease burden compared with that in mice receiving a nontargeting control. In vitro, the combination of venetoclax with epcoritamab induced superior killing of CLL cells than either agent alone. These data support the investigation of epcoritamab in combination with BTKis or venetoclax to consolidate responses and target emergent drug-resistant subclones.
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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 [98]
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BCL2i-Based Therapies and Emerging Resistance in Chronic Lymphocytic Leukemia
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The Impact of Minimal Residual Disease Measurement in the Management of Chronic Lymphocytic Leukemia
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Epcoritamab in B-cell malignancies: current status and prospects
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The Role of Tumor Microenvironment and Targeted Therapy in Chronic Lymphocytic Leukemia
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Immunotherapy in Chronic Lymphocytic Leukemia
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Self-citation
- Authors
- 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., Chen, J., Reilly, E. B., Epling-Burnette, P. K., Szafer-Glusman, E., Sun, C., & Wiestner, A.
- Affiliations
- National Institutes of Health (US)
- Genmab (United States) (US)
- Genmab (Netherlands) (NL)
- AbbVie (United States) (US)
- 4AbbVie Inc, North Chicago, IL
- 5AbbVie Inc, Sunnyvale, CA
- Corresponding author
- Wiestner, Adrian
- ORCID
- Venue
- Blood Advances
- Publisher
- American Society of Hematology
- Published
- 2023-07-28
- Volume
- 7
- Issue
- 15
- Pages
- 4089-4101
- ISSN
- 2473-9529 (ISSN-L)
- 2473-9537
- PMC
- PMC10388733
- OpenAlex
- W4377563779
- Cited by
- 43
- References
- 68
- Citations by year
- 2026: 9 · 2025: 18 · 2024: 12 · 2023: 4
- FWCI
- 7.45
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Blood Advances (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute
- Topics
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Keywords
- epcoritamab, chronic lymphocytic leukemia, BTK inhibitors, venetoclax, BCL-2 inhibition, combination therapy, T cell effector function, cytotoxicity, drug resistance, patient-derived xenografts, T cell expansion, relapsed CLL
- MeSH terms
- Animals, Antineoplastic Agents, Humans, Leukocytes, Mononuclear, Sulfonamides, Leukemia, Lymphocytic, Chronic, B-Cell, Antibodies, Bispecific, Bridged Bicyclo Compounds, Heterocyclic, Proto-Oncogene Proteins c-bcl-2, Mice
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