title: Intracellular delivery system for antibody-Peptide drug conjugates.
abstract: Antibodies armed with biologic drugs could greatly expand the therapeutic potential of antibody-drug conjugates for cancer therapy, broadening their application to disease targets currently limited by intracellular delivery barriers. Additional selectivity and new therapeutic approaches could be realized with intracellular protein drugs that more specifically target dysregulated pathways in hematologic cancers and other malignancies. A multifunctional polymeric delivery system for enhanced cytosolic delivery of protein drugs has been developed that incorporates endosomal-releasing activity, antibody targeting, and a biocompatible long-chain ethylene glycol component for optimized safety, pharmacokinetics, and tumor biodistribution. The pH-responsive polymeric micelle carrier, with an internalizing anti-CD22 monoclonal targeting antibody, effectively delivered a proapoptotic Bcl-2 interacting mediator (BIM) peptide drug that suppressed tumor growth for the duration of treatment and prolonged survival in a xenograft mouse model of human B-cell lymphoma. Antitumor drug activity was correlated with a mechanistic induction of the Bcl-2 pathway biomarker cleaved caspase-3 and a marked decrease in the Ki-67 proliferation biomarker. Broadening the intracellular target space by more effective delivery of protein/peptide drugs could expand the repertoire of antibody-drug conjugates to currently undruggable disease-specific targets and permit tailored drug strategies to stratified subpopulations and personalized medicines.
authors: Department of Bioengineering, University of Washington, Seattle, Washington, USA; Current address: BioMarin Pharmaceutical, Novato, California, USA.
authors: Geoffrey Y
authors: GY
authors: Berguig
authors: Department of Bioengineering, University of Washington, Seattle, Washington, USA.
authors: Anthony J
authors: AJ
authors: Convertine
authors: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors: Shani
authors: S
authors: Frayo
authors: Department of Bioengineering, University of Washington, Seattle, Washington, USA.
authors: Hanna B
authors: HB
authors: Kern
authors: Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, Washington, USA; Current Address: Department of Biochemistry, University of Illinois, Urbana, Illinois, USA.
authors: Erik
authors: E
authors: Procko
authors: Department of Bioengineering, University of Washington, Seattle, Washington, USA.
authors: Debashish
authors: D
authors: Roy
authors: Department of Bioengineering, University of Washington, Seattle, Washington, USA.
authors: Selvi
authors: S
authors: Srinivasan
authors: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors: Daciana H
authors: DH
authors: Margineantu
authors: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors: Garrett
authors: G
authors: Booth
authors: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; Current Address: Seattle Genetics, Bothell, Washington, USA.
authors: Maria Corinna
authors: MC
authors: Palanca-Wessels
authors: Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, Washington, USA.
authors: David
authors: D
authors: Baker
authors: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors: David
authors: D
authors: Hockenbery
authors: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors: Oliver W
authors: OW
authors: Press
authors: Department of Bioengineering, University of Washington, Seattle, Washington, USA. Electronic address: stayton@uw.edu.
authors: Patrick S
authors: PS
authors: Stayton
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D017209:Apoptosis / Q000187:drug effects; D001682:Biological Availability; D015415:Biomarkers; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000096:biosynthesis; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D004355:Drug Stability; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D051379:Mice; D008823:Micelles; D010455:Peptides; D011108:Polymers / Q000737:chemistry; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry / Q000378:metabolism; D014018:Tissue Distribution; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D015415:Biomarkers; D018796:Immunoconjugates; D008823:Micelles; D010455:Peptides; D011108:Polymers; D019253:Proto-Oncogene Proteins c-bcl-2; D045304:Cytochromes c