monomethylauristatin-f and maytansinol

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.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antigens, CD; Bacteriocins; CD8-Positive T-Lymphocytes; Cells, Cultured; Graft Rejection; Humans; Immunocompetence; Immunosuppressive Agents; Immunotoxins; Integrin alpha Chains; Intestines; Islets of Langerhans Transplantation; Lymphocyte Depletion; Male; Maleimides; Maytansine; Mice; Mice, Inbred C57BL; Oligopeptides; Postoperative Complications