Engineered antibodies: new possibilities for brain PET?

Abstract

Almost 50 million people worldwide are affected by Alzheimer's disease (AD), the most common neurodegenerative disorder. Development of disease-modifying therapies would benefit from reliable, non-invasive positron emission tomography (PET) biomarkers for early diagnosis, monitoring of disease progression, and assessment of therapeutic effects. Traditionally, PET ligands have been based on small molecules that, with the right properties, can penetrate the blood-brain barrier (BBB) and visualize targets in the brain. Recently a new class of PET ligands based on antibodies have emerged, mainly in applications related to cancer. While antibodies have advantages such as high specificity and affinity, their passage across the BBB is limited. Thus, to be used as brain PET ligands, antibodies need to be modified for active transport into the brain. Here, we review the development of radioligands based on antibodies for visualization of intrabrain targets. We focus on antibodies modified into a bispecific format, with the capacity to undergo transferrin receptor 1 (TfR1)-mediated transcytosis to enter the brain and access pathological proteins, e.g. amyloid-beta. A number of such antibody ligands have been developed, displaying differences in brain uptake, pharmacokinetics, and ability to bind and visualize the target in the brain of transgenic mice. Potential pathological changes related to neurodegeneration, e.g. misfolded proteins and neuroinflammation, are suggested as future targets for this novel type of radioligand. Challenges are also discussed, such as the temporal match of radionuclide half-life with the ligand's pharmacokinetic profile and translation to human use. In conclusion, brain PET imaging using bispecific antibodies, modified for receptor-mediated transcytosis across the BBB, is a promising method for specifically visualizing molecules in the brain that are difficult to target with traditional small molecule ligands.

Antibodies for the Treatment of Brain Metastases, a Dream or a Reality?

“…The brain uptake of the molecule was of 0.88% ID/brain. The value is within the boundaries of the brain uptake of other drugs that are active in the brain [44,90,91]. However, the mAb demonstrated a high affinity towards the receptor.…”

Brain delivery of biologics using a cross‐species reactive transferrin receptor 1 VNAR shuttle

“…Receptor mediated transport across the BBB is increasingly viewed as an attractive approach to considerably enhance brain concentrations of therapeutic antibodies and other biologics. However, there have been perceived limitations of this approach at the level of pharmacokinetics, 9,11 dosing, 28 side effects, 12 and translatability to larger species. 13,14 The present study assesses the utility of a single domain VNAR antibody (TXB2) to TfR1 to deliver a radiolabeled Aβ antibody into the brain of AβPP transgenic mice.…”

The Added Value of Diagnostic and Theranostic PET Imaging for the Treatment of CNS Tumors

“…With increasing knowledge of cancer biology, crucial molecular targets have been identified, leading to the development of a wide range of targeted therapeutic pharmaceuticals, of which the receptor tyrosine kinase inhibitory drugs are the most rapidly expanding class [16,131]. Receptor tyrosine kinases (RTKs), including epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), and platelet-derived growth factor receptor (PDGFR), among others, are transmembrane proteins that have been shown to serve a pivotal role in cell growth-related signal transduction.…”

“…Attempts to overcome an intact BBB for improved drug delivery have a long history in which chemical disruption via the hyperosmotic solution mannitol was the first, followed by applying other drugs that influence passive diffusion or active transport mechanisms [141,142]. In another approach, therapeutic pharmaceuticals are attached to molecules naturally transported across the barrier (i.e., viral vectors, nanoparticles, liposomes, exosomes), and by using transporter or receptor (e.g., transferrin receptor) ligands, such as how transport is done with an anti-amyloid-beta antibody modified into a bispecific format with the capacity to undergo transferrin receptor 1 (TfR1)-mediated transcytosis for Alzheimer's disease [131]. Other attempts for improved drug delivery include mechanical disruption techniques such as by applying radiotherapy, microwaves, or ultrasound (e.g., high-intensity focused ultrasound, HIFU), or by using novel technical approaches such as stereotaxic injection into the cerebrospinal fluid or convection-enhanced delivery (CED).…”