Applications of nanobodies in brain diseases

Abstract

Nanobodies are antibody fragments derived from camelids, naturally endowed with properties like low molecular weight, high affinity and low immunogenicity, which contribute to their effective use as research tools, but also as diagnostic and therapeutic agents in a wide range of diseases, including brain diseases. Also, with the success of Caplacizumab, the first approved nanobody drug which was established as a first-in-class medication to treat acquired thrombotic thrombocytopenic purpura, nanobody-based therapy has received increasing attention. In the current review, we first briefly introduce the characterization and manufacturing of nanobodies. Then, we discuss the issue of crossing of the brain-blood-barrier (BBB) by nanobodies, making use of natural methods of BBB penetration, including passive diffusion, active efflux carriers (ATP-binding cassette transporters), carrier-mediated influx via solute carriers and transcytosis (including receptor-mediated transport, and adsorptive mediated transport) as well as various physical and chemical methods or even more complicated methods such as genetic methods via viral vectors to deliver nanobodies to the brain. Next, we give an extensive overview of research, diagnostic and therapeutic applications of nanobodies in brain-related diseases, with emphasis on Alzheimer’s disease, Parkinson’s disease, and brain tumors. Thanks to the advance of nanobody engineering and modification technologies, nanobodies can be linked to toxins or conjugated with radionuclides, photosensitizers and nanoparticles, according to different requirements. Finally, we provide several perspectives that may facilitate future studies and whereby the versatile nanobodies offer promising perspectives for advancing our knowledge about brain disorders, as well as hopefully yielding diagnostic and therapeutic solutions.

A few good reasons to use nanobodies for cancer treatment

“…Again, nanobodies could come to the rescue thanks to their smaller size and different physicochemical properties [57]. The group of Pierre Lafaye demonstrated that nanobodies are superior to conventional antibodies when it comes to diffusion into fixed brain tissues [58], or as BBB‐permeable probes in vivo that are able to detect both intracellular and extracellular brain targets [59].…”

Endogenous pathology in tauopathy mice progresses via brain networks

“…We used a previously characterized, fluorescently conjugated nanobody directed against human tau (pS422) (VHH-A2-488), which stains Alzheimer's and P301L tauopathy mouse brain (24) comparably to AT8 (16), and an antip-tau monoclonal antibody widely used to monitor pathology (25)(26)(27)(28). Because of their smaller size and other inherent features (29,30), we expected VHH-A2-488 to better penetrate and diffuse through large tissue volumes-essential for serial two-photon tomography (STPT). We optimized a protocol for permeabilization, immunolabeling and washing compatible with whole brain staining of p-tau (Fig.…”

Ultrahigh-potent and broadly neutralizing anti-CD4 trimeric nanobodies inhibit HIV-1 infection by inducing CD4 conformational alteration

“…Following washes, ow cytometry was employed for subsequent analysis. 19. Model To facilitate subsequent molecular dynamics simulations, we diligently crafted three pivotal molecular structures: Nb 457 -Fc, Nb 457 -Nb HSA -Nb 457 , and the HIV-1 CH058 gp120.…”

“…Importantly, our data, as well as other reports, indicated that nanobodies offered a unique binding mode to target proteins when compared to traditional antibodies, leading to remarkably potent neutralization against viral infections [15][16][17] . Following the approval of Caplacizumab, the rst camelderived nanobody, for marketing in 2018 18 , numerous nanobodies currently have been in clinical trials including ALX-0651 for tumors, ALX-0171 for RSV virus, and ALX for in ammation 12,13,19 , underscoring the signi cant therapeutic potential of nanobodies. Thus far, anti-CD4 nanobodies have been developed and utilized for in vivo CD4 cell tracing 20 , while no anti-CD4 nanobodies have yet been developed for the therapeutic purpose of neutralizing HIV-1 infection.…”