Targeting the undruggable: emerging technologies in antibody delivery against intracellular targets

• Published in: Expert opinion on drug delivery Vol. 17; no. 9; p. 1189
• Main Authors: Niamsuphap, Suchada, Fercher, Christian, Kumble, Sumukh, Huda, Pie, Mahler, Stephen M, Howard, Christopher B
• Format: Journal Article
• Language: English
• Published: England 01.09.2020
• Subjects: Antibodies, Monoclonal - administration & dosage; Biological Transport; Cell-Penetrating Peptides - metabolism; Drug Delivery Systems; Endosomes - metabolism; Humans; Nanoparticles - chemistry; Polymers - chemistry; lipid-based platforms; Intracellular antibody delivery; endosomal escape; polymeric carriers; cell-penetrating peptides
• ISSN: 1744-7593
• DOI: 10.1080/17425247.2020.1781088

Monoclonal antibodies have been utilized in clinical and basic research for the treatment of various malignancies. Whilst all therapeutically approved monoclonal antibodies or fragments thereof are directed against cell-surface receptors or proteins of the human secretome, intracellular antigen targeting strategies still await translation into the clinic. This contradicts the notion of antibodies being the magic bullet concept as many cancer targets are out of reach. This review provides a summary of intracellular translocation strategies that were successfully employed for antibody delivery in preclinical studies. Examples encompass a variety of different approaches such as polymeric and lipid-based nanoparticles (NP), biomimetics, bispecific antibody constructs, the use of cell-penetrating peptides, as well as various sophisticated combinations thereof. We will further discuss endosomal escape as the major bottleneck in functional intracellular transport and provide suggestions on how to overcome current challenges. Despite significant advances in protein delivery technologies, reports of highly efficient transport vehicles are sparse when systemically applied . Consequently, more detailed mechanistic studies are needed to identify and optimize the molecular 'Achilles heel' of individual methodologies. Ultimately, to target intracellular proteins that have been undruggable in the past, a combination of strategies may be required.