Intracellular Delivery System for Antibody-Peptide Drug Conjugates

被引：33

作者：

Berguig, Geoffrey Y. ^{[1
]}

Convertine, Anthony J. ^{[1
]}

Frayo, Shani ^{[2
]}

Kern, Hanna B. ^{[1
]}

Procko, Erik ^{[3
,4
]}

Roy, Debashish ^{[1
]}

Srinivasan, Selvi ^{[1
]}

Margineantu, Daciana H. ^{[2
]}

Booth, Garrett ^{[2
]}

Palanca-Wessels, Maria Corinna ^{[2
]}

Baker, David ^{[3
,4
]}

Hockenbery, David ^{[2
]}

Press, Oliver W. ^{[2
]}

Stayton, Patrick S. ^{[1
]}

机构：

[1] Univ Washington, Dept Bioengn, Seattle, WA 98195 USA

[2] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA

[3] Univ Washington, Dept Biochem, Seattle, WA 98195 USA

[4] Univ Washington, Inst Prot Design, Seattle, WA 98195 USA

来源：

MOLECULAR THERAPY | 2015年 / 23卷 / 05期

关键词：

FRAGMENTATION CHAIN TRANSFER; FREE-RADICAL POLYMERIZATION; B-CELL LYMPHOMAS; IN-VIVO EFFICACY; BCL-2; FAMILY; CANCER-THERAPY; RAFT; OLIGONUCLEOTIDES; NANOPARTICLES; COPOLYMERS;

D O I：

10.1038/mt.2015.22

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 [微生物学]; 090105 [作物生产系统与生态工程];

摘要：

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 BcI-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 BcI-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.

引用

页码：907 / 917

页数：11

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