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Review
. 2025 Aug 6;14(15):5534.
doi: 10.3390/jcm14155534.

Bispecific Antibodies-A New Hope for Patients with Diffuse Large B-Cell Lymphoma

Affiliations
Review

Bispecific Antibodies-A New Hope for Patients with Diffuse Large B-Cell Lymphoma

Romeo Gabriel Mihaila et al. J Clin Med. .

Abstract

T-cell-engaging antibodies are a promising new type of treatment for patients with refractory or relapsed (R/R) diffuse large B-cell lymphoma, which has changed the prognosis and evolution of these patients in clinical trials. Bispecific antibodies (BsAbs) bind to two different targets (B and T lymphocytes) at the same time and in this way mimic the action of CAR (chimeric antigen receptor) T-cells. They are the T-cell-engaging antibodies most used in practice and are a solution for patients who do not respond to second- or later-line therapies, including chemoimmunotherapy, followed by salvage chemotherapy and hematopoietic stem cell transplantation. They are a therapeutic option for patients who are ineligible for CAR T-cell therapy and are also active in those with prior exposure to CAR T-cell treatment. A remarkable advantage of BsAbs is their rapid availability, even if the disease progresses rapidly, unlike CAR T-cell treatment, and they avoid the practical and financial challenges raised by autologous CAR T-cell therapies. CAR-T has been proven to have better efficacy compared to BsAbs, but cytokine release syndrome and neurotoxicity have appeared significantly more frequently in patients treated with CAR T-cells. The possibility of combining BsAbs with chemotherapy and their administration for relapses or as a frontline therapy is being studied to increase their efficacy. BsAbs are a life-saving therapy for many patients with diffuse large B-cell malignant non-Hodgkin's lymphoma (NHL) who have a poor prognosis with classical therapies, but are not without adverse effects and require careful monitoring.

Keywords: CAR T-cell; T-cell-engaging antibodies; bispecific antibodies; blinatumomab; epcoritamab; glofitamab; mosunetuzumab.

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Conflict of interest statement

The authors state that there are no conflicts of interest regarding the publication of this article.

Figures

Figure 1
Figure 1
Mechanism of action of bispecific antibodies (BsAbs) in lymphoma and associated adverse effects. BsAbs simultaneously bind to CD3 on T-cells and CD20 on lymphoma cells, facilitating targeted T-cell-mediated cytotoxicity. AKI, acute kidney injury; BsAb, bispecific antibody; CD3, cluster of differentiation 3; CD20, cluster of differentiation 20; CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome; IFN-γ, interferon gamma; IL-2, interleukin-2; IL-6, interleukin-6; TNF-α, tumor necrosis factor alpha; TLS, tumor lysis syndrome. Created in Biorender. Samuel B. Todor (2025) https://app.biorender.com/illustrations/6862abe589408258b34db174.
Figure 2
Figure 2
Mechanisms of T-cell activation against malignant B-cells. Left: Normal T-cell response via MHC-I antigen presentation to the TCR/CD3 complex. Middle: CAR T-cell therapy bypasses MHC-I by recognizing CD19 through a synthetic receptor with intracellular signaling domains. Right: Bispecific antibodies (BsAbs) simultaneously bind to CD3 on T-cells and CD20 on B-cells, redirecting T-cell cytotoxicity via perforin and granzyme release. Abbreviations: BsAb, bispecific antibody; CAR, chimeric antigen receptor; CD3, cluster of differentiation 3; CD19, cluster of differentiation 19; CD20, cluster of differentiation 20; MCH-I, major histocompatibility complex class I; TCR, T-cell receptor. Created in Biorender. Samuel B. Todor (2025) https://app.biorender.com/illustrations/6864f9f2d1fadb4f5400e863.
Figure 3
Figure 3
Schematic representation of the immunopathogenesis of ICANS (immune effector cell-associated neurotoxicity syndrome). Activated T-cells release inflammatory cytokines (IL-1, IL-6, and TNF-α), leading to endothelial activation, blood–brain barrier (BBB) disruption, and capillary leakage. This cascade facilitates T-cell infiltration into the CNS, triggering neuroinflammation, cerebral edema, reactive astrocytes, neuronal dysfunction, and—occasionally—demyelination in severe cases. Abbreviations: ICANS, immune effector cell-associated neurotoxicity syndrome; BBB, blood–brain barrier; IL-1, interleukin-1; IL-6, interleukin-6; TNF-α, tumor necrosis factor alpha; CNS, central nervous system. Generated with biorender.com.

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