Antibody-siRNA conjugates: drugging the undruggable for anti-leukemic therapy

ABSTRACT

Introduction: 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.

KEYWORDS:

• Antibodies
• antibody-siRNA conjugates (ARCs)
• acute lymphoblastic leukemia (ALL)
• acute myeloid leukemia (AML)
• antibody dependent cell cytotoxicity (ADCC)
• bispecific antibodies
• cancer therapy
• chronic lymphoblastic leukemia (CLL)
• chronic myeloid leukemia (CML)
• complement dependent cytotoxicity (CDC)
• non-hodgkin lymphoma (NHL)
• RNA induced silencing complex (RISC)
• bispecific antibodies
• RNA interference technology (RNAi)
• small interfering RNAs (siRNAs)
• small molecules inhibitors (SMI)
• targeted delivery

Article highlights

• Targeted antibody therapies are preferably safe and efficacious than chemotherapy treatment regimens for leukemia.

• Limited differentially expressed cell surface receptors (antigens) demand the use of antibody-siRNA conjugate based approaches.

• Ongoing siRNA based clinical trials have confirmed the non-specific accumulation (off-targeting) of therapeutic RNAs at undesired tissue locations.

• There is critical unmet need of an optimized cargo carrier such as antibody-siRNA conjugates (ARCs) platform that is efficient in siRNA stabilization, cellular internalization, reduced off targeting, and selective delivery into cancer cells.

This box summarizes key points contained in the article

Acknowledgments

I personally thank Dr. Sanchita Bhatnagar, Dr. Ron Taylor, Dr. Gururaj Shivange, James Zachary Jones, Robert Haggart, William Bachmann and Christina Kostka here at Department of Biochemistry and Molecular Genetics for critical reading of the manuscript. I would also like to thank Dr. John Majercak and Dr. Ertan Eryilmaz for insightful discussion.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

J Tushir-Singh’s laboratory is supported by the University of Virginia’s faculty start-up funds, The rector and visitors of the university of Virginia.