title: Antibody-Targeted Chemotherapy for the Treatment of Melanoma.
abstract: Antibody-directed chemotherapy (ADC) offers an advantage over conventional chemotherapy because it provides antibody-directed targeting, with resultant improvement in therapeutic efficacy and reduced toxicity. Despite extensive research, with notable exceptions, broad clinical application of ADC remains elusive; major hurdles include the instability of antibody-chemotherapy linkers and reduced tumor toxicity of the chemotherapy when bound to the antibody. To address these challenges, we have developed a platform technology that utilizes the nab-paclitaxel formulation of paclitaxel, Abraxane, in which hydrophobic paclitaxel is suspended in 130-nm albumin nanoparticles and thus made water-soluble. We have developed a method to noncovalently coat the Abraxane nanoparticle with recombinant mAbs (anti-VEGF, bevacizumab) and guide Abraxane delivery into tumors in a preclinical model of human A375 melanoma. Here, we define the binding characteristics of bevacizumab and Abraxane, demonstrate that the chemotherapy agent retains its cytotoxic effect, while the antibody maintains the ability to bind its ligand when the two are present in a single nanoparticle (AB160), and show that the nanoparticle yields improved antitumor efficacy in a preclinical human melanoma xenograft model. Further data suggest that numerous therapeutic monoclonal IgG1 antibodies may be utilized in this platform, which has implications for many solid and hematologic malignancies. Cancer Res; 76(13); 3954-64. ©2016 AACR.
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Nevala
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Buhrow
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Knauer
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Reid
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Elena A
authors.initials: EA
authors.lastname: Atanasova
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota. Division of Oncology, Mayo Clinic, Rochester, Minnesota. Markovic.svetomir@mayo.edu.
authors.forename: Svetomir N
authors.initials: SN
authors.lastname: Markovic
mesh_terms: D000068196:Albumin-Bound Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis; D000068258:Bevacizumab / Q000008:administration & dosage / Q000494:pharmacology*; D015153:Blotting, Western; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000068196:Albumin-Bound Paclitaxel; D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000068258:Bevacizumab