Comparison of CD3e Antibody and CD3e-sZAP Immunotoxin Treatment in Mice Identifies sZAP as the Main Driver of Vascular Leakage

Biomedicines

Christene A. Huang¹  Zhirui Wang¹  Sophie G. Cressman²  Alice Baek²  Hannah Yu²  Amit Sharma²  Sanggu Kim²  Prosper N. Boyaka²  Eunsoo Kim²  Alan Kim²  Namal P. M. Liyanage²  Rajni Kant Shukla²  Hyewon Choi²  Shihyoung Kim²  John C. Reneau³ 

[1] Department of Surgery, University of Colorado Denver Anschutz Medical Campus, Division of Plastic & Reconstructive Surgery, 12700 East 19th Avenue, Aurora, CO 80045, USA;Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210, USA;Division of Hematology, The Ohio State University, Columbus, OH 43210, USA;

关键词: CD3e monoclonal antibody;    CD3e immunotoxin;    T-cell depletion;    saporin;    saporin–streptavidin (sZAP);    vascular leakage syndrome;   

DOI  :  10.3390/biomedicines10061221

来源: DOAJ

【 摘 要 】

Anti-CD3-epsilon (CD3e) monoclonal antibodies (mAbs) and CD3e immunotoxins (ITs) are promising targeted therapy options for various T-cell disorders. Despite significant advances in mAb and IT engineering, vascular leakage syndrome (VLS) remains a major dose-limiting toxicity for ITs and has been poorly characterized for recent “engineered” mAbs. This study undertakes a direct comparison of non-mitogenic CD3e-mAb (145-2C11 with Fc-silent^TM murine IgG1: S-CD3e-mAb) and a new murine-version CD3e-IT (saporin–streptavidin (sZAP) conjugated with S-CD3e-mAb: S-CD3e-IT) and identifies their distinct toxicity profiles in mice. As expected, the two agents showed different modes of action on T cells, with S-CD3e-mAb inducing nearly complete modulation of CD3e on the cell surface, while S-CD3e-IT depleted the cells. S-CD3e-IT significantly increased the infiltration of polymorphonuclear leukocytes (PMNs) into the tissue parenchyma of the spleen and lungs, a sign of increased vascular permeability. By contrast, S-CD3e-mAbs-treated mice showed no notable signs of vascular leakage. Treatment with control ITs (sZAP conjugated with Fc-silent isotype antibodies) induced significant vascular leakage without causing T-cell deaths. These results demonstrate that the toxin portion of S-CD3e-IT, not the CD3e-binding portion (S-CD3e-mAb), is the main driver of vascular leakage, thus clarifying the molecular target for improving safety profiles in CD3e-IT therapy.

【 授权许可】

Unknown