title: Efficient elimination of CD103-expressing cells by anti-CD103 antibody drug conjugates in immunocompetent mice.
abstract: CD103 plays an important role in the destruction of islet allografts, and previous studies found that a CD103 immunotoxin (M290-Saporin, or M290-SAP) promoted the long-term survival of pancreatic islet allografts. However, systemic toxicity to the host and the bystander effects of M290-SAP obscure the underlying mechanisms of action and restrict its clinical applications. To overcome these shortcomings, anti-CD103 M290 was conjugated to different cytotoxic agents through cleavable or uncleavable linkages to form three distinct antibody-drug conjugates (ADCs): M290-MC-vc-PAB-MMAE, M290-MC-MMAF, and M290-MCC-DM1. The drug-to-antibody ratio (DAR) and the purity of the ADCs were determined by HIC-HPLC and SEC-HPLC, respectively. The binding characteristics, internalization and cytotoxicity of M290 and the corresponding ADCs were evaluated in vitro. The cell depletion efficacies of the various M290-ADCs against CD103-positive cells were then evaluated in vivo. The M290-ADCs maintained the initial binding affinity for the CD103-positive cell surface antigen and then quickly internalized the CD103-positive cell. Surprisingly, all M290-ADCs potently depleted CD103-positive cells in vivo, with high specificity and reduced toxicity. Our findings show that M290-ADCs have potent and selective depletion effects on CD103-expressing cells in immunocompetent mice. These data indicate that M290-ADCs could potentially serve as a therapeutic intervention to block the CD103/E-cadherin pathway.
authors.affiliation: Department of General Surgery, The 2nd Affiliated Hospital of Harbin Medical University, 246 Xufu Road, Harbin, Heilongjiang Province 150086, China.
authors.forename: Yuanyi
authors.initials: Y
authors.lastname: Mang
authors.affiliation: Department of General Surgery, The 2nd Affiliated Hospital of Harbin Medical University, 246 Xufu Road, Harbin, Heilongjiang Province 150086, China.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of General Surgery, The 2nd Affiliated Hospital of Harbin Medical University, 246 Xufu Road, Harbin, Heilongjiang Province 150086, China.
authors.forename: Zhaolin
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: Department of General Surgery, The 2nd Affiliated Hospital of Harbin Medical University, 246 Xufu Road, Harbin, Heilongjiang Province 150086, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of General Surgery, The 2nd Affiliated Hospital of Harbin Medical University, 246 Xufu Road, Harbin, Heilongjiang Province 150086, China.
authors.forename: Zhengjie
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of General Surgery, The 2nd Affiliated Hospital of Harbin Medical University, 246 Xufu Road, Harbin, Heilongjiang Province 150086, China. Electronic address: Doctorzhanglei@gmail.com.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D058846:Antibodies, Monoclonal, Murine-Derived; D015703:Antigens, CD / Q000276:immunology; D001430:Bacteriocins / Q000737:chemistry; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D002478:Cells, Cultured; D006084:Graft Rejection / Q000209:etiology / Q000517:prevention & control*; D006801:Humans; D007121:Immunocompetence; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D000922:Immunotoxins / Q000008:administration & dosage* / Q000737:chemistry; D039001:Integrin alpha Chains / Q000037:antagonists & inhibitors* / Q000276:immunology; D007422:Intestines / Q000276:immunology; D016381:Islets of Langerhans Transplantation; D008212:Lymphocyte Depletion; D008297:Male; D008301:Maleimides / Q000737:chemistry; D008453:Maytansine / Q000031:analogs & derivatives / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000737:chemistry; D011183:Postoperative Complications / Q000517:prevention & control*
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D015703:Antigens, CD; D001430:Bacteriocins; D007166:Immunosuppressive Agents; D000922:Immunotoxins; D039001:Integrin alpha Chains; C552082:M290SAP; D008301:Maleimides; D009842:Oligopeptides; C091367:alpha E integrins; C562224:maytansinol; C513576:monomethylauristatin F; C020411:microcin; D008453:Maytansine; C495575:monomethyl auristatin E
keywords: Antibody–drug conjugates; CD103/E-cadherin pathway; CD8 T lymphocytes; Integrin