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.

Department(s)

Materials Science and Engineering

Keywords and Phrases

antibody peptide conjugate; antineoplastic agent; caspase 3; CD22 antibody BIM protein conjugate; copolymer; cytochrome c; Ki 67 antigen; polypeptide; protein bcl 2; unclassified drug; antibody conjugate; biological marker; cytochrome c; micelle; monoclonal antibody; peptide; polymer; protein bcl 2, animal experiment; animal model; animal tissue; antineoplastic activity; Article; B cell lymphoma; cancer inhibition; cancer survival; cell assay; cell population; controlled study; disease marker; dose response; drug cytotoxicity; drug delivery system; drug determination; drug distribution; drug formulation; drug half life; drug mechanism; drug megadose; drug overdose; drug structure; enzyme modification; human; human cell; large cell lymphoma; low drug dose; micelle; molecular dynamics; mouse; nonhuman; pH measurement; plasma clearance; protein cleavage; protein secretion; survival rate; survival time; time to maximum plasma concentration; tumor xenograft; animal; apoptosis; bioavailability; biosynthesis; chemistry; disease model; drug effects; drug screening; drug stability; Lymphoma, B-Cell; metabolism; mortality; pathology; tissue distribution; tumor cell line; tumor volume, Animals; Antibodies, Monoclonal; Apoptosis; Biological Availability; Biomarkers; Cell Line, Tumor; Cytochromes c; Disease Models, Animal; Drug Delivery Systems; Drug Stability; Humans; Immunoconjugates; Lymphoma, B-Cell; Mice; Micelles; Peptides; Polymers; Proto-Oncogene Proteins c-bcl-2; Tissue Distribution; Tumor Burden; Xenograft Model Antitumor Assays

International Standard Serial Number (ISSN)

1525-0016

Document Type

Article - Journal

Document Version

Citation

File Type

text

Language(s)

English

Rights

© 2015 Nature Publishing Group, All rights reserved.

PubMed ID

25669432

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