Efficient elimination of CD103-expressing cells by anti-CD103 antibody drug conjugates in immunocompetent mice

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-ADC5 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-ADC5 potently depleted CD103-positive cells in vivo, with high specificity and reduced toxicity. Our findings show that M290-ADC5 have potent and selective depletion effects on CD103-expressing cells in immunocompetent mice. These data indicate that M290-ADC5 could potentially serve as a therapeutic intervention to block the CD103/E-cadherin pathway. (C) 2014 Elsevier B.V. All rights reserved.