Antibodies inside of a cell can change its outside: Can intrabodies provide a new therapeutic paradigm?

Abstract

Challenges posed by complex diseases such as cancer, chronic viral infections, neurodegenerative disorders and many others have forced researchers to think beyond classic small molecule drugs, exploring new therapeutic strategies such as therapy with RNAi, CRISPR/Cas9 or antibody therapies as single or as combination therapies with existing drugs. While classic antibody therapies based on parenteral application can only reach extracellular targets, intracellular application of antibodies could provide specific advantages but is so far little recognized in translational research. Intrabodies allow high specificity and targeting of splice variants or post translational modifications. At the same time off target effects can be minimized by thorough biochemical characterization. Knockdown of cellular proteins by intrabodies has been reported for a significant number of disease-relevant targets, including ErbB-2, EGFR, VEGFR-2, Metalloproteinase MMP2 and MMP9, β-amyloid protein, α-synuclein, HIV gp120, HCV core and many others. This review outlines the recent advances in ER intrabody technology and their potential use in therapy.

TRIM21 and the Function of Antibodies inside Cells

“…Introduction of intrabodies usually requires expression of DNA plasmids encoding antibody sequences within the target cell, either by transfection or by gene therapy approaches using adeno-associated virus in the whole animal [34]. Chemical modification to aid delivery or covalent fusion of antibody molecules with cell-penetrating peptides, such as HIV-1 TAT, have also been used, as well as modification with amino acid motifs which support localisation to distinct subcellular compartments, for example endoplasmic reticulum retention using the KDEL motif [35][36][37]. The efficiency of some of these mechanisms of introduction has been questioned [22].…”

Porcine parvovirus VP1/VP2 on a time series epitope mapping: exploring the effects of high hydrostatic pressure on the immune recognition of antigens

“…The PLA 2 domain is responsible for crucial steps in the PPV infection cycle by facilitating the release of the virus near the nucleus after successful endosome formation and prior to the activation of nuclear localization signaling. Numerous studies since the 1980s have investigated the latter event following the demonstration that microinjections of antibodies can interfere with intracellular antigens [44]. The inhibition of antigen function by the binding of antibodies to their antigen within endosomes is dependent upon factors such as exposure, identity and, primarily, pH.…”

Therapeutic Antibodies against Intracellular Tumor Antigens

“…An intradiabody that simultaneously enabled the knockdown of VEGF-R2 and Tie-2 was able to reduce both tumor growth and angiogenesis in vivo ( 28 ). Intrabody technology is overviewed in depth by recent reviews including Marschall and Dübel ( 29 ).…”