Central Nervous System Delivery of Antibodies and Their Single-Domain Antibodies and Variable Fragment Derivatives with Focus on Intranasal Nose to Brain Administration

Abstract

IgG antibodies are some of the most important biopharmaceutical molecules with a high market volume. In spite of the fact that clinical therapies with antibodies are broadly utilized in oncology, immunology and hematology, their delivery strategies and biodistribution need improvement, their limitations being due to their size and poor ability to penetrate into tissues. In view of their small size, there is a rising interest in derivatives, such as single-domain antibodies and single-chain variable fragments, for clinical diagnostic but also therapeutic applications. Smaller antibody formats combine several benefits for clinical applications and can be manufactured at reduced production costs compared with full-length IgGs. Moreover, such formats have a relevant potential for targeted drug delivery that directs drug cargo to a specific tissue or across the blood–brain barrier. In this review, we give an overview of the challenges for antibody drug delivery in general and focus on intranasal delivery to the central nervous system with antibody formats of different sizes.

Nanobodies against SARS-CoV-2 reduced virus load in the brain of challenged mice and neutralized Wuhan, Delta and Omicron Variants

“…Although our hypothesis regarding Nbs access to the brain needs to be confirmed by radiolabeling biodistribution assays, our data suggest that intranasal administration of a cocktail of Nbs could be used to prevent or treat COVID-19 encephalitis. This statement is further supported by other studies that have reported that Nbs can reach the brain after intranasal administration [59][60][61]. To our knowledge, this is the first report of SARS-CoV-2 replication reduction in the brain after a Nb treatment in a mouse model.…”

Camelid Single-Domain Antibodies: Promises and Challenges as Lifesaving Treatments

“…Several VHHs isolated from naïve llama or immune libraries (e.g., FC5, FC44, anti-IGF1R5, and anti-VCAM VHHs), alone, in bispecific, liposome-mediated, or Fc-fused formats were able to improve the delivery of target peptides/cargo up to 10-30-fold when compared to the control with no VHH [129,130]. A VHH-Fc construct with a longer half-life in blood circulation led to improved delivery of the peptide although the advantage of small VHH size is compromised [121]. Extensive research to identify ideal targets and to improve antibody engineering is still required to reach the maximum delivery of antibody-cargo into the brain.…”

“…The strong target specificity of antibody-based therapeutics is a major advantage compared to small molecule drugs for the treatment of neurodegenerative diseases. However, the delivery of protein therapeutics to the brain has proven challenging, since only a small fraction of injected mAbs (0.1-0.2%) reaches the brain due to the tight blood-brain barrier (BBB) [121]. Bispecific antibodies targeting transferrin receptor have facilitated the transmigration process by shuttling binding proteins across the BBB resulting in a 5-10-fold increase in brain uptake [122].…”

Alternative Routes of Administration for Therapeutic Antibodies—State of the Art

“…It consists of administering drugs in the olfactory region of the nose, by inhalation, from where they may transfer to the brain through the epithelial layer and via neuronal bundles that project to the olfactory bulb. The “nose-to-brain” route is under preclinical evaluation for Abs [ 133 ].…”