Targeting T cells with tetravalent bispecific antibodies for the treatment of graft-versus-host disease
Abstract: Allogeneic hematopoietic stem cell transplantation is an established treatment for hematological malignancies and some genetic diseases. Acute graft-versus-host disease (GVHD) is the most common and debilitating side effect with poor survival rates of 5% to 30% for severe cases. In this ma...
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| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-01-01
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| Series: | Blood Advances |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2473952924005561 |
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| Summary: | Abstract: Allogeneic hematopoietic stem cell transplantation is an established treatment for hematological malignancies and some genetic diseases. Acute graft-versus-host disease (GVHD) is the most common and debilitating side effect with poor survival rates of 5% to 30% for severe cases. In this manuscript, we describe a tetravalent T-cell–engaging bispecific antibody (BsAb) based on the immunoglobulin G-[L]-single-chain variable fragment (IgG-[L]-scFv) platform, with all 4 binding domains specific for CD3. In vitro, picomolar concentrations of the CD3×CD3 BsAb induced potent lysis of activated CD4 and CD8 T cells. In immunodeficient mice, in which human T cells induced xenogeneic GVHD, administration of 0.1 μg BsAb per dose depleted the majority of T cells from the peripheral blood, and 10 μg per dose completely reversed established GVHD and achieved a 100% survival rate. In mice bearing NALM6-luc xenografts, treatment with CD3×CD19 BsAb and activated human T cells induced complete remission of the leukemia, and all treated mice developed GVHD by 50 days after treatment. CD3×CD3 BsAb (3-30 μg doses) reversed clinical signs of GVHD, allowing long term follow-up beyond 250 days. T cells were undetectable by polymerase chain reaction in 4 of 5 mice in the 30 μg CD3×CD3 BsAb group 180 days after leukemia injection, and complete necropsies on day 259 revealed no evidence of human T cells or leukemia cells. Curing GVHD allows for long-term follow-up of tumor response heretofore impossible in humanized mouse models. Further studies are warranted to determine whether the CD3×CD3 BsAb has potential for treating clinical GVHD and other autoimmune diseases in humans. |
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| ISSN: | 2473-9529 |