title: Antibody-siRNA conjugates: drugging the undruggable for anti-leukemic therapy.
abstract: Generating effective RNAi-based therapies with the potential to achieve leukemia remission remains critical unmet need. Despite a growing number of leukemia clinical trials, tissue specific delivery of therapeutic siRNA is a major roadblock in translating its clinical potential. The most recent reports in the antibody-siRNA-conjugates (ARCs) field add new dimensions to leukemic therapy, where a covalently ligated therapeutic antisense-RNA with the potential to repress the oncogenic transcript is selectively delivered into the cancer cells. Despite ARC localization to leukemic cells due to high affinity antigen-antibody interactions, multiple challenges exist to unlock the therapeutic potential of siRNA targeting. Areas covered: This review focuses on antibody and siRNA-based therapies for leukemia as well as potential antibody engineering-based strategies to generate an optimal ARC platform. Expert opinion: In vitro and clinical results have revealed that non-targeted delivery and inefficient cellular internalization of therapeutic siRNA are major contributing factors for the lack of efficacy in leukemia patients. Rational antibody design and selective protein engineering with the potential to neutralize siRNA charge, stabilize ARC complex, restrict off-targeted delivery, optimize endosomal escape, and extend serum half-life will generate clinically relevant leukemic therapies that are safe, selective, and effective.
authors.affiliation: a Laboratory of Novel Biologics, Department of Biochemistry & Molecular Genetics , University of Virginia Cancer Center, University of Virginia School of Medicine , Charlottesville , VA , USA.
authors.forename: Jogender
authors.initials: J
authors.lastname: Tushir-Singh
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000627:therapeutic use*; D006801:Humans; D018796:Immunoconjugates / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D007938:Leukemia / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*
chemical_list: D000906:Antibodies; D018796:Immunoconjugates; D034741:RNA, Small Interfering
keywords: Antibodies; RNA induced silencing complex (RISC); RNA interference technology (RNAi); acute lymphoblastic leukemia (ALL); acute myeloid leukemia (AML); antibody dependent cell cytotoxicity (ADCC); antibody-siRNA conjugates (ARCs); bispecific antibodies; cancer therapy; chronic lymphoblastic leukemia (CLL); chronic myeloid leukemia (CML); complement dependent cytotoxicity (CDC); non-hodgkin lymphoma (NHL); small interfering RNAs (siRNAs); small molecules inhibitors (SMI); targeted delivery