Targeting T cells with tetravalent bispecific antibodies for the treatment of graft-versus-host disease Journal Article
| Authors: | Espinosa-Cotton, M.; Hoseini, S. S.; Miranda, I. C.; Herrick, J.; Cheung, N. K. V. |
| Article Title: | 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 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. © 2024 by The American Society of Hematology. |
| Keywords: | immunohistochemistry; controlled study; survival analysis; leukemia; survival rate; unclassified drug; overall survival; nonhuman; flow cytometry; follow up; polymerase chain reaction; cd3 antigen; cd8+ t lymphocyte; cell proliferation; t lymphocyte; animal cell; mouse; animal tissue; cell survival; apoptosis; animal experiment; animal model; cyclophosphamide; dexamethasone; immunoglobulin g; xenograft; cd4+ t lymphocyte; scoring system; cell isolation; glycosylation; graft versus host reaction; remission; chimeric antigen receptor; high performance liquid chromatography; tumor growth; cytokine release; lethargy; antibody; t lymphocyte activation; interleukin 15; cell killing; physical chemistry; cytokine release syndrome; interleukin 15 receptor; article; tetravalent bispecific antibody |
| Journal Title: | Blood Advances |
| Volume: | 9 |
| Issue: | 1 |
| ISSN: | 2473-9529 |
| Publisher: | American Society of Hematology |
| Date Published: | 2025-01-14 |
| Start Page: | 116 |
| End Page: | 126 |
| Language: | English |
| DOI: | 10.1182/bloodadvances.2022009187 |
| PUBMED: | 39293079 |
| PROVIDER: | scopus |
| PMCID: | PMC11742559 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK author: Nai-Kong V. Cheung -- Source: Scopus |
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