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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| Format: | Article |
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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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| author | Madelyn Espinosa-Cotton Sayed Shahabuddin Hoseini Ileana C. Miranda John Herrick Nai-Kong V. Cheung |
| author_facet | Madelyn Espinosa-Cotton Sayed Shahabuddin Hoseini Ileana C. Miranda John Herrick Nai-Kong V. Cheung |
| author_sort | Madelyn Espinosa-Cotton |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-637f2765b3af49128bd4fa45dc75c7cb |
| institution | DOAJ |
| issn | 2473-9529 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Blood Advances |
| spelling | doaj-art-637f2765b3af49128bd4fa45dc75c7cb2025-08-20T02:51:00ZengElsevierBlood Advances2473-95292025-01-019111612610.1182/bloodadvances.2022009187Targeting T cells with tetravalent bispecific antibodies for the treatment of graft-versus-host diseaseMadelyn Espinosa-Cotton0Sayed Shahabuddin Hoseini1Ileana C. Miranda2John Herrick3Nai-Kong V. Cheung4Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NYDepartment of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NYLaboratory of Comparative Pathology, Memorial Sloan Kettering Cancer Center, New York, NYDepartment of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NYDepartment of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY; Correspondence: Nai-Kong V. Cheung, Department of Pediatrics, Memorial Sloan Kettering Cancer Center, 1275 York Ave, Box 170, New York, NY 10065;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.http://www.sciencedirect.com/science/article/pii/S2473952924005561 |
| spellingShingle | Madelyn Espinosa-Cotton Sayed Shahabuddin Hoseini Ileana C. Miranda John Herrick Nai-Kong V. Cheung Targeting T cells with tetravalent bispecific antibodies for the treatment of graft-versus-host disease Blood Advances |
| title | Targeting T cells with tetravalent bispecific antibodies for the treatment of graft-versus-host disease |
| title_full | Targeting T cells with tetravalent bispecific antibodies for the treatment of graft-versus-host disease |
| title_fullStr | Targeting T cells with tetravalent bispecific antibodies for the treatment of graft-versus-host disease |
| title_full_unstemmed | Targeting T cells with tetravalent bispecific antibodies for the treatment of graft-versus-host disease |
| title_short | Targeting T cells with tetravalent bispecific antibodies for the treatment of graft-versus-host disease |
| title_sort | targeting t cells with tetravalent bispecific antibodies for the treatment of graft versus host disease |
| url | http://www.sciencedirect.com/science/article/pii/S2473952924005561 |
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