Next Article in Journal
Efficacy of 15 nm Gold Nanoparticles for Image-Guided Gliosarcoma Radiotherapy
Previous Article in Journal
Recent Advances in Combating Bacterial Infections by Using Hybrid Nano-Systems
Previous Article in Special Issue
Recent Advances in Gold Nanomaterials for Photothermal Therapy
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
JNT
Volume 4
Issue 4
10.3390/jnt4040020
jnt-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Enhancing Antibody Exposure in the Central Nervous System: Mechanisms of Uptake, Clearance, and Strategies for Improved Brain Delivery

by
Kelly Schwinghamer
and
Teruna J. Siahaan
*
Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, KS 66046, USA
*
Author to whom correspondence should be addressed.
J. Nanotheranostics 2023, 4(4), 463-479; https://doi.org/10.3390/jnt4040020
Submission received: 26 July 2023 / Revised: 22 September 2023 / Accepted: 25 September 2023 / Published: 2 October 2023
(This article belongs to the Special Issue Exclusive Papers of the Editorial Board Members)
Browse Figure
Versions Notes

Abstract

:
Antibodies (mAbs) are attractive molecules for their application as a diagnostic and therapeutic agent for diseases of the central nervous system (CNS). mAbs can be generated to have high affinity and specificity to target molecules in the CNS. Unfortunately, only a very small number of mAbs have been specifically developed and approved for neurological indications. This is primarily attributed to their low exposure within the CNS, hindering their ability to reach and effectively engage their potential targets in the brain. This review discusses aspects of various barriers such as the blood–brain barrier (BBB) and blood–cerebrospinal fluid (CSF) barrier (BCSFB) that regulate the entry and clearance of mAbs into and from the brain. The roles of the glymphatic system on brain exposure and clearance are being described. We also discuss the proposed mechanisms of the uptake of mAbs into the brain and for clearance. Finally, several methods of enhancing the exposure of mAbs in the CNS were discussed, including receptor-mediated transcytosis, osmotic BBB opening, focused ultrasound (FUS), BBB-modulating peptides, and enhancement of mAb brain retention.

1. Introduction

Monoclonal antibodies (mAbs) have emerged as promising therapeutic and diagnostic candidates for a wide range of diseases due to their ability to target specific molecules with high affinity. They offer advantages including low toxicity, long systemic half-lives, and the capacity for large-scale production with high purity. However, the development of mAbs for central nervous system (CNS) diseases is hampered by the limited access to the CNS caused by protective barriers surrounding the brain such as the blood–brain barrier (BBB). These barriers pose challenges in delivering mAbs to their intended targets within the brain at concentrations necessary for their optimal efficacy. Moreover, mAbs administered directly into the cerebrospinal fluid (CSF) are rapidly cleared from the CNS to the systemic circulation, with reported half-lives from minutes to hours [1,2,3]. Despite these obstacles, recent FDA approvals for treatments of neurological disorders, such as Leqembi® (lecanemab) and Aduhelm® (aducanumab) for Alzheimer’s Disease (AD), have demonstrated the potential of mAbs for treating brain disorders. Both mAbs have shown the ability to reduce amyloid plaques in the early stage of AD [4,5]; however, the high intravenous doses of mAb required for achieving sufficient doses in the brain for its efficacy have been associated with damage to the blood–brain barrier (BBB) [6]. Therefore, many researchers are investigating new methods to safely improve the efficiency of mAb delivery to the brain. This review aims at enhancing our understanding of antibody brain exposure by investigating their uptake and clearance from the central nervous system (CNS), while also exploring the current state-of-the-art mAb delivery methods. By delving into these aspects, we strive to improve antibody brain exposure, ultimately enhancing their potential therapeutic efficacy.

1.1. The Blood–Brain Barrier

The blood–brain barrier (BBB) comprises the largest interface between the central nervous system (CNS) and the systemic circulation, serving as a protective barrier that regulates the exchange of substances between the brain and the peripheral parts of the body (Figure 1A). The BBB is formed by a collaborative effort between endothelial cells, pericytes, and surrounding astrocytic endfeet, which collectively create a specialized structure known as the neurovascular unit (NVU). This unit is characterized by the close association of endothelial cells and pericytes and they share a common basement membrane [7], while being supported by the enveloping astrocytic endfeet. Together, these components contribute to the establishment and maintenance of the BBB’s selective permeability and functional integrity.
The molecular permeability of the BBB is primarily hindered by brain capillary endothelial cells (BECs), while pericytes and astrocytes in the neurovascular unit (NVU) contribute to structural stability and release chemical factors that maintain BBB integrity [7,8,9]. BECs impose stringent restrictions on both transcellular and paracellular transport of molecules (Figure 1A). Transcellular transport is limited due to the lack of fenestrations, abundance of mitochondria, low rates of transcytosis, and expression of efflux transporters [10,11]. Moreover, tight protein–protein interactions form tight junctions—adherens junctions—and desmosomes between BECs, severely impeding paracellular transport across the BBB. These BBB properties present a formidable obstacle to the delivery of therapeutic and diagnostic agents to the brain. Indeed, approximately 98% of small molecule drugs and mostly all macromolecule therapeutics are unable to penetrate the CNS through the BBB [10,12].

1.2. The Blood–Cerebrospinal Fluid (CSF) Barrier (BCSFB)

The choroid plexus (CP) serves as a part of a barrier known as the blood–cerebrospinal fluid (BCSFB) barrier, establishing an additional interface within the CNS for the passage of molecules. The CP is constructed of a highly vascularized stroma with specialized epithelial cells and fenestrated capillaries. Positioned strategically in each of the four ventricles of the brain, the CP plays a crucial role in CSF production. The CP actively transports ions, nutrients, and metabolism products between the blood and CSF, contributing to the maintenance of a chemically balanced environment in the CNS.
After its production by CP epithelial cells, CSF circulates from the lateral ventricles to the third ventricle through the intraventricular foramen and, subsequently, reaches the fourth ventricle via the cerebral aqueduct. From the fourth ventricle, CSF continues to circulate in the subarachnoid space lining around the brain, as well as through the spinal cord central canal. The subarachnoid space is defined by a barrier of epithelial-like arachnoid cells that separates the CSF from the fenestrated vasculature present in the dura. As a result, these arachnoid barrier cells also contribute to the BCSFB.
Similar to the BECs of the BBB, the epithelial cells of the CP and arachnoid barrier cells are joined together using tight and adherens junctions that restrict paracellular transport into the CSF. Restricted paracellular transport allows cellular transporters to control the distribution of solutes on both sides of the barrier (Figure 1A). BSCFB cells also express a wide variety of transporters, which are often distributed asymmetrically between the basolateral and apical membranes, carefully regulating chemical homeostasis [13]. Additionally, like the BECs of the BBB, CP epithelial cells contain a high number of mitochondria to meet the energetic demands of transepithelial transport [13].

2. Mechanisms of Antibody Uptake into the CNS

Although mAbs possess high specificity, a long systemic half-life, and minimal off-target effects, their potential as therapeutic candidates for neurological diseases is impeded by the restrictive CNS barrier. The physicochemical properties of mAbs (i.e., large size, high hydrogen bonding potential, charge) prevent them from traversing through the BBB to reach potential targets within the CNS. Nevertheless, peripheral administration of mAbs has demonstrated their presence in the CNS with CNS-to-plasma or CNS-to-serum ratios ranging from 0.1% to 0.3% [14,15,16,17,18]. The precise mechanisms by which mAbs in the systemic circulation achieve CNS exposure are speculative, however, several theories have been proposed.
Several mAbs have been approved for use in patients with brain diseases such as Alzheimer’s disease (AD), multiple sclerosis (MS), and brain tumors (i.e., glioblastoma, neuroblastoma) (Table 1) [19,20,21]. Several approved therapeutic mAbs have functions to control biological events in the peripheral tissues or outside the brain; thus, they do not need to cross the BBB into the brain for their biological activities. For example, an MS drug, Natalizumab (Tysabri), has activity to inhibit the infiltration of activated immune cells into the brain by blocking immune cell adhesion on the BBB endothelial cells [22]. The two successful mAbs (i.e., Aducanumab, Lecanemab) that target amyloid beta plaques in the brain have been approved for treating AD patients; these mAbs presumably have to cross the BBB to clear the amyloid beta plaques in the brain [4,23,24]. In contrast, several clinical trials of mAbs for the remyelination of axons in MS patients, such as VX15/2503, anti-LINGO-1 (Opicinumab), sHIgM22, and anti-Nogo-A, were terminated due to the lack of efficacy [25,26,27,28]. Similarly, the phase 2 clinical trial of anti-Tau mAb (8E12) in AD patients was stopped due to the lack of mAb efficacy [29]. In some cases, the delivery of mAb to the brain was not efficient because of the difficulty of crossing the BBB from the systemic circulation. In addition, there is still a lack of comprehensive and quantitative studies to compare the efficiency of various methods to deliver mAbs into the brain.

2.1. Crossing the BCSFB

To measure brain concentrations, researchers often rely on CSF concentrations to act as a surrogate for widespread brain exposures; however, doing so may produce overestimations of mAb concentrations within the brain parenchyma. Numerous studies have highlighted that molecules administered directly into the CSF experience rapid clearance and achieve minimal penetration into the brain tissue [1,2,3,30]. As a result, measuring antibody CSF concentrations may serve as a representation of molecular transport across the BCSFB but may not provide an accurate prediction of mAb brain deposition and therapeutic efficacy.
Evidence to support the BCSFB crossing of mAbs includes the relative “leakiness” of the BCSFB compared to the BBB. While the BCSFB and BBB have distinct permeability profiles based on specific transporter expression on their respective membranes, the BCSFB has been found to be more permeable compared to the BBB [31]. This increased permeability manifests as leakage of plasma proteins across the barrier and lower electrical resistance of the cellular barrier [31,32].

2.2. Non-Specific Endocytosis

In a recent study conducted by Van De Vyver et al., pharmacokinetics in the brains of healthy rats were modeled to analyze the effects of non-targeting mAbs administered via intravenous (IV) or intracerebroventricular (ICV) route [33]. Pathway analysis from their study suggested that antibody exposure in the interstitial fluid (ISF) of the brain is predominantly mediated by mAbs traversing the BBB rather than entering the ISF directly from the CSF, regardless of route of administration [33]. While some researchers have speculated that transcytosis of IgG antibodies may be facilitated by receptors on brain endothelial cells, such as the neonatal Fc receptor (FcRn), several studies have refuted this hypothesis [15,16,34]. Alternatively, other researchers have proposed that antibody uptake across the BBB occurs non-specifically via endocytic vessels in the brain [34,35].
Researchers supporting the non-specific uptake of antibodies across the BBB have highlighted that the magnitude of circulating mAb uptake into the CNS (0.1–0.3%) is comparable to other endogenous circulating proteins, such as serum albumin [35,36]. In line with this notion, several studies have reported that increasing antibody dosage leads to an increase in CNS exposure in a non-saturating fashion [34,37]. Conversely, an independent investigation examined the transport of IgG antibodies across human brain microvascular endothelial cells in an in vitro BBB model and discovered that antibody transport was saturable and reliant on macropinocytosis [36]. These findings collectively indicate that the uptake of IgG occurs through non-specific, charge-based adsorption of IgG to the negatively charged endothelial cell surface, followed by subsequent macropinocytosis. The relationship between charge and brain uptake has been demonstrated in other studies for mAbs [34,38] as well as other macromolecules such as albumin [39].

2.3. Antibody Clearance from the CNS

The administration of most therapeutic mAbs for neurological disorders is performed intravenously. This is because strategies to bypass the BBB through delivery directly into the CSF of the CNS have demonstrated that mAbs rapidly efflux from the CSF back into the serum with limited penetration into the brain parenchyma. This is also true for the administration of mAbs directly into the brain parenchyma, where rapid clearance half-lives have been reported and minimal diffusion throughout the whole brain tissue [40,41]. The rapid clearance of direct CNS delivery, therefore, causes these more invasive administration methods to have similar mAb exposure profiles as the IV administration. Therefore, it is imperative to improve our understanding of the potential mAb clearance mechanisms limiting their brain exposure in order to develop long-acting therapeutics for the brain.

2.4. Neonatal Fc Receptor

The neonatal Fc receptor (FcRn) is a class of Fc receptors recognized for its crucial role in antibody transport and recycling. FcRn facilitates passive immunity transfer from mother to young by enabling the transcytosis of IgG antibodies across the placental and intestinal mucosa barrier. The receptor is expressed on the cell surface of various cell types, including endothelial cells, epithelial cells, and antigen-presenting cells [42]. A study by Schlachetzki et al. [43] demonstrated that FcRn is expressed on the microvasculature in the brain, raising inquiries about its involvement in the transport of IgG antibodies across the BBB.
While FcRn may facilitate the bidirectional transport of antibodies across a barrier, multiple studies have found no evidence of FcRn contributing to the influx of antibodies from blood to the brain, leading to higher CNS exposure [15,16,34,44]. However, Pardridge and colleagues have suggested that FcRn may mediate brain-to-blood efflux of IgG and have demonstrated Fc-dependent elimination of IgG from the brain after intracranial administration in rats [40,45]. Similar studies by Cooper et al. observed reduced clearance of an IgG with attenuated FcRn binding following intracranial administration in rats [46]. Additionally, brain clearance of endogenous amyloid beta following intravenous administration of anti-amyloid beta (anti-Aβ) mAb was found to be reduced in FcRn−/− mice [47].
While investigations by Balthasar and co-workers have challenged the idea of FcRn-mediated brain efflux, [15,16] it is important to note that study design differences may have contributed to these conflicting findings. Balthasar’s studies tracked whole brain concentrations following intravenous administration of radiolabeled mAbs in FcRn knockout mice and observed no difference in brain-to-blood AUC ratios between FcRn−/− mutants and control animals [15,16]; however, whole-brain concentrations may inaccurately reflect antibody concentrations in the parenchyma, where FcRn-mediated efflux across the BBB is speculated to occur and may reflect CSF concentrations from mAb crossing the BCSFB, as discussed in previous sections.

3. The Glymphatic System and Bulk Convective Flow

The lymphatic vasculature plays a vital role in clearing ISF, along with its constituent proteins and solutes that are not absorbed across postcapillary venules, while also serving to maintain hydrostatic pressure [48]. This function is essential for overall tissue homeostasis. Intriguingly, despite its high metabolic rate and the remarkable sensitivity of neurons and glial cells to changes in the extracellular environment, the brain lacks a lymphatic vascular system [48]. To address this disparity, Nedergaard and colleagues proposed an alternative waste clearance system in the brain, resembling the lymphatic clearance systems in peripheral tissues [49]. They coined this system the ”glymphatic system”, which serves as a mechanism for efficient waste clearance in the brain.
The glymphatic system is connected to perivascular space (PVS) and aquaporin-4 (AQP4) and it operates by utilizing the transport of CSF in the perivascular spaces (PVSs) of the brain (Figure 1B). The pial of the artery in parenchyma is connected to the Virchow-Robin spaces (VRS) that surround the arteries, venules, and capillaries to form donut-like tunnel spaces called PVS (Figure 1B) [50]. PVS is constructed by a combination of smooth muscle and vascular endothelial cells at the inner wall while the outer wall is constructed of the astrocyte endfeet. Arterioles that penetrate the brain parenchyma contain PSV which are finally fused basal lamina containing extracellular matrix proteins (ECM), including laminin, fibronectin, and collagen. This allows the CSF to influx along the peri-arterial space. In this case, CSF can enter the brain parenchyma via PVS to mix with ISF for delivering nutrients or clearing metabolites.
The glymphatic system delivers nutrients to the parenchyma via periarterial CSF influx as well as removes metabolism waste via perivenous routes for clearance of cell debris and unwanted large metabolites (i.e., proteins) using AQP4 on astrocytes. These regions consist of CSF-filled spaces between the basement membranes of brain endothelial cells and the astrocytic endfeet (Figure 1A). The proposed pathway for fluid flow and waste removal begins with CSF from the subarachnoid space moving along periarterial spaces into the brain (Figure 1B). CSF then leaves the periarterial spaces to mix with ISF within the brain parenchyma before being transported via convective flow to perivenous spaces (Figure 1B). The CSF in perivenous spaces will then drain into the peripheral lymphatic system. The functionality of this system relies on the continuous flow of fluid through the brain tissue extracellular space with the help of aquaporin-4 (AQP4) on the astrocytic endfeet near the basement membrane of brain endothelial cells (Figure 1A). The bulk flow of convective movement propels fluid through the brain parenchyma, aiding in the clearance of waste products into the CSF-filled perivenous spaces for eventual peripheral lymphatic clearance.
Nedergaard’s key experiments that contributed to the discovery of this system involved tracking the movement of fluorescently or radioactively labeled tracer molecules with various molecular weights following intraparenchymal and intracisternal administration. After intracisternal injection, they observed the CSF movement in perivascular spaces and in the ESC of the parenchyma characteristic of the glymphatic system described above [49]. Notably, molecules of significant molecular weight differences cleared from the parenchyma at similar rates, indicating that convective bulk flow, rather than diffusion, is responsible for their clearance [49]. Additional studies have also provided support for glymphatic clearance mechanisms [49,51,52,53,54,55]. The proposed bulk convective flow within the ECS, as suggested by the glymphatic system, presents a potential mechanism for antibody clearance after distribution in the parenchyma.

4. Diffusion

The proposed concept of convective flow facilitating clearance from the brain parenchyma, as suggested by the glymphatic system, faces challenges from several researchers who contend that molecular transport in the extracellular space (ECS) of the parenchyma is primarily driven by diffusion. These researchers argue that the ECS of the brain parenchyma is intricately structured, and characterized by the presence of numerous cell bodies and processes with diverse sizes and shapes [56]. Additionally, the ECS is composed of a complex solution of proteins and glycosaminoglycans, imparting gel-like properties to the fluid [57]. Consequently, these factors lead researchers to assert that convective flow, facilitated by AQP4, would not be adequate to overcome the substantial hydraulic resistance exhibited by the brain.
Numerous studies provide evidence for the diffusive transfer of solutes through the ECS of the brain parenchyma. Contrary to the findings of Iliff et al. [49] for supporting the glymphatic system, experiments conducted in Verkman’s laboratory had demonstrated that the transfer of fluorescent dextrans in the brain parenchyma was size-dependent and not dependent on cardiorespiratory rate or AQP4-gene deletion [58]. Similar studies by Pizzo and colleagues utilized the same infusion rate/site and duration as the key experiments that established the concepts of the glymphatic system [49,59]. However, they found that diffusion was the predominant transport process governing distribution into the ECS following administration into the CSF [59]. If diffusion is indeed the primary mechanism responsible for waste clearance from the gel-like ECS, the clearance rate of antibodies would be affected by a gel filtration effect influenced by factors such as molecular shape, charge, and size.

5. Antibody Delivery Strategies into the CNS

A comprehensive understanding of the mechanisms governing mAb uptake and clearance in the brain is pivotal for researchers seeking to optimize delivery and retention strategies, ultimately maximizing exposure profiles of mAb in the brain. Many researchers concentrate their efforts on enhancing the permeation of mAbs across the BBB. These efforts include enhancing mAb delivery through transcellular pathways—often utilizing receptor-mediated transcytosis (RMT) delivery—or paracellular pathways by disrupting the tight junction proteins that bind these BBB cells together (Figure 1A). Additionally, novel approaches are being explored to promote mAb retention, allowing for gradual accumulation within the brain over time. While no delivery method has been used to achieve FDA approval of antibodies to date, several strategies have demonstrated remarkable potential. The continued development of these strategies may hold significant implications for the treatment of neurological disorders.

5.1. Receptor-Mediated Transcytosis (Trojan Horse Method)

Some circulating endogenous proteins are capable of traversing the BBB through specific receptor transporters on the endothelial cells of the BBB; such as transferrin, insulin, and leptin [60]. The discovery of these receptor-mediated transport (RMT) systems has led to so-called “Trojan Horse” delivery systems for antibodies, where antibodies are genetically modified to bind to an RMT system to induce transfer across the BBB [60]. Initial studies proved that antibodies targeting the transferrin receptor in rats [61,62], or the human insulin receptor [63], demonstrated the ability to undergo RMT to increase brain exposure.
Antibodies directed against human insulin receptors (HIRs) or transferrin receptors (TfRs) have been effectively employed as antibody drug conjugates (ADCs) to facilitate the transport of smaller peptides or proteins across the highly restrictive BBB. In one study, a vasoactive intestinal peptide (VIP) was conjugated to an anti-transferrin mAb (OX-26) via an avidin–biotin linkage [64]. When applied topically to brain surface vessels, VIP alone is a potent cerebral vasodilator but it is incapable of crossing the BBB independently. However, the infusion of the OX-26-VIP conjugate in rats resulted in a significant 65% increase in cerebral blood flow compared to the controls of OX-36 or VIP administered alone [64]. Another study employed chemical conjugation to link nerve growth factor (NGF) to OX-26, which, when tested in an extra-cranial anterior eye transplant model, exhibited enhanced survival rates of both cholinergic and non-cholinergic neurons compared to unconjugated OX-26 and NGF controls [65]. Additionally, ADCs employing RMT mAbs have been utilized for diagnostic purposes in a primate study to examine amyloid levels in the brain [66].
Bispecific antibodies targeting the TfR or HIR have also been developed to increase antibody-BBB penetration and exert potential therapeutic effects. The first antibody engineered of this kind was tetravalent, wherein the carboxyl terminus of a bivalent genetically engineered antibody against the human insulin receptor (HIR) was fused with two anti-amyloid β (anti-Aβ) single-chain variable fragments (ScFv) [45]. However, several studies have indicated that increasing the affinity/avidity of antibodies against transferrin or insulin leads to substantial accumulation and degradation within brain capillary endothelial cells (BCECs), with limited transport into the brain tissue beyond the capillaries [67,68,69]. Therefore, Yu et al. investigated the correlation between TfR affinity and brain uptake and were the first to examine monovalent bispecific antibodies targeting the TfR [70]. Their research revealed that decreasing the TfR affinity resulted in an increase in brain exposure. They also demonstrated the increase in BBB transport of a genetically engineered bispecific antibody targeting TfR and β-secretase (BACE-1) compared to that of a monospecific anti-BACE-1 mAb [70]. BACE-1 is an enzyme important for processing Aβ peptides associated with AD. Supporting these findings, monovalent binding of mAb to TfR increased transport across the BBB compared to bivalent TfR binding; this monovalent binding influenced lysosome sorting of the mAb [71].
TfR mAbs and HIR mAbs face several safety concerns for their development. While these antibodies are developed to target epitopes on receptors separate from iron or insulin binding locations, [72] they possess the potential for both agonistic and antagonistic effects on the receptors. For example, hypoglycemia was observed in primates who received high doses of HIRmAb-IDUA (human α-L-iduronidase) [73]; however, no such effect was observed at low doses or when infused in humans [74]. Additionally, studies have indicated that TfR mAbs may lower iron uptake, either through antagonist effects or through depletion of TfR on cell membranes [75].
These promising findings have sparked hope for the development of effective treatments for CNS diseases, particularly mucopolysaccharidosis type II [76,77,78] and AD [79]. With the ongoing clinical trials for RG6102 as a novel antibody therapeutic for AD, the ability of the RMT brain shuttle technology to facilitate the crossing of the blood–brain barrier and target amyloid plaques in AD mouse models has been demonstrated [71,80]. These advancements hold great potential for the future of CNS disease treatment, paving the way for improved patient outcomes and enhanced quality of life.

5.2. Osmotic BBB Opening

Experiments in the 1970s demonstrated the reversible opening of the BBB in rabbits through intracarotid administrations of hyperosmolar concentrated electrolyte solutions [81,82]. It is believed that the reversible opening of the paracellular pathways (Figure 1A) of the BBB was a result of the osmotic withdrawal of water from BBB endothelial cells, causing cell shrinkage and tight junction separation. The increase in molecular permeability to the brain via the paracellular pathways of the BBB has been shown to be size-dependent, with higher permeability of small molecules compared to larger molecules [83]. In addition, the osmotic BBB opening (OBBBO) or BBB disruption (BBBD) method has demonstrated the ability to increase the delivery of proteins with large molecular weights, including albumin, antibodies such as Fab fragments, immunoglobulin G (IgG), and immunoglobulin M (IgM) [84,85,86,87,88,89,90,91,92]. Following BBBD, an increase in the CNS concentration of endogenous neutralizing IgG was observed in primates that were immunized against measles; this result demonstrates the potential of BBBD to improve efficacy of immunotherapy in treating infections in the brain [87]. Additionally, exogenous IgG delivery was increased with BBBD following intravenous administration of the mAb in rats [86].
There are some safety concerns that have been observed with the BBBD method. BBBD produces a long-term opening of the BBB to allow circulating large molecules (e.g., albumin and fibrinogen) to enter the brain and produce toxic effects in the brain tissues [93,94]. One study found that the nerve damage caused by the uptake of these plasma proteins into the brain may be irreversible [95]. Preclinical studies in rats have demonstrated that BBBD induces microglial activation and a sterile inflammatory response in the brain [96], and alters cerebral blood flow [97]. Additionally, clinical studies using BBBD to deliver oncology agents to patients found a 13% incidence of seizures associated with the delivery method [95].

5.3. Focused Ultrasound Microbubbles

Focused ultrasound (FUS) is a technique that utilizes acoustic energy to increase BBB permeability in focal regions of the brain. This method was developed based on the findings that ultrasound waves can cause cavitation and collapse of tiny gas-filled bubbles in fluids. In tissues, focused ultrasound (FUS) can cause cavitation within blood vessels, which can cause various effects based on the frequency and intensity of radiation. The effects of FUS on the brain have been studied since the 1960s, where the high frequencies used could induce the BBB opening but also resulted in lesions within the parenchyma [98]. In 1995, studies were conducted to refine the sonication parameters to induce BBB opening while minimizing tissue damage [99]. It was later discovered that combining FUS with IV administration of tiny gaseous microbubbles (MB) can drastically lower the acoustic parameters needed to facilitate BBB opening without damaging the tissue [100]. MB help reduce acoustic parameters by acting as cavitation sites under FUS, where the mechanical forces disrupt endothelial cells of the BBB to allow molecules to enter the brain.
Several studies have investigated the size of the BBB opening from FUS-MB using fluorescently labeled dextran molecules [101,102]. A constant acoustic pressure of 0.57 MPa delivered 3 kDa and 70 kDa dextran molecules across the BBB but not 2000 kDa dextran [101]. A parallel study found that increasing the acoustic pressure to 0.84 MPa could facilitate the delivery of 2000 kDa dextran [102]; however, pressure at 0.84 MPa was found to induce inertial cavitation and cause microhemorrhages in the brain [102]. When examining the brain permeability of liposomes of sizes ranging from 55 to 200 nm using FUS-MB, increasing the MB dose from 0.1 μL/g to 0.5 μL/g significantly enhanced the delivery of the 200 nm liposomes. These results indicate that the extent of BBB opening with FUS-MB is determined by both the acoustic parameters and the injected dose (ID) of MB.
A combination of modulating the ID of MB and acoustic parameters has allowed researchers to deliver mAbs to the brain using FUS-MB. Numerous preclinical studies in mice demonstrate the ability of FUS-MB to effectively deliver antibodies to the brain with minimal tissue damage, including an anti-HER2 mAb [103] and a mAb against the dopamine D4 receptor [104]. Antibody delivery with FUS-MB has shown promise in enhancing the therapeutic efficacy of mAbs for brain diseases. For example, FUS-MB resulted in a 5.5-fold increase in delivery of anti-pyroglutamate-3 anti-Aβ mAb to the brain of APP/PS1dE9 mice, a model for AD, and improved spatial learning and memory in the animals at a faster rate [105]. In a xenograft mouse model of high-grade glioma from a patient, FUS-MB increased the delivery of a tumor-targeting antibody to localized tumor regions of the brain. Due to the success of preclinical studies, several clinical safety studies have been evaluated in humans for brain tumors [106] and AD [107]. These clinical safety studies have demonstrated FUS-MB to be a well-tolerated potential delivery method in humans, making this a promising approach for treating CNS disorders with mAbs.

5.4. BBB-Modulating Peptides

One approach to improve the paracellular permeability of the BBB is by disrupting protein–protein interactions between the BBB endothelial cells using small cadherin-derived BBB modulator (BBBM) peptides. These peptides block cadherin–cadherin interactions, temporarily increasing the porosity of the BBB to enable the transport of molecules from the blood into the brain. In vitro studies have demonstrated BBBM activity of these peptides by inhibiting calcium-dependent reaggregation [108], lowering transepithelial electrical resistance (TEER) [109,110], and increasing paracellular transport of 14C-mannitol in tight junction-forming cell monolayers [110]. Additionally, BBBMs in animal models (mice and rats) have demonstrated increased in vivo brain delivery of small molecules (i.e., anticancer agents [111,112], mannitol [111,113], gadopentetic acid [113,114,115]), medium-sized peptides [116], and large molecules, including Brain-Derived Neurotrophic Factor (BDNF) (13 kDa) [117,118], IRDye800CW PEG (25 kDa) [114,115], albumin (67 kDa) [116,119], and IgG mAb (150 kDa) [119,120]. Successful in vivo delivery of molecules has been detected with Magnetic Resonance Imaging (MRI), Near-IR Fluorescence (NIRF) imaging, mass spectrometry, and radioactivity counts.
Co-dosage of an IgG mAb with BBBM peptides in mice resulted in a significant 2–4-fold increase in mAb deposition within the brain compared to the administration of mAb alone [119,120]. The extent of increase varied depending on the specific BBBM peptide used, with cyclic BBBM peptides demonstrating higher enhancement compared to linear counterparts [120]. Multiple injections of BBBM after one administration of mAb can significantly enhance mAb brain deposition compared to only one administration of BBBM along with mAb. While studies have demonstrated the improved therapeutic efficacy of BDNF through enhanced brain deposition using BBBM peptides in mouse models of multiple sclerosis (MS) and Alzheimer’s disease (AD) [117,118], no investigations have been conducted to determine the therapeutic impact of enhanced antibody brain deposition achieved with these peptides.
To date, no safety concerns have been reported with the BBBM peptides. Repeat administration of peptides in mice did not result in weight loss or change in locomotive activity [121]. In addition, this study also showed no astrogliosis and inflammation in the brains of mice treated with BBBM [121]. Unlike other methods such as BBBD, BBBM enhanced paracellular permeability and did not alter cerebral blood flow [114]. Notably, although BBBMs have the ability to increase albumin brain deposition [116,119], which can be toxic to the brain [93], minimal toxicity has been observed. One potential reason for the minimal toxicity is that the opening of the BBB by BBBM peptides is transient and reversible. The BBB opening was observed between 1 and 4 h for a small molecule [113,114] (Gd-DTPA, MW~500 Da) and less than 40 min for a large molecule (Galbumin, MW ~65 kDa) [116]. Furthermore, BBBMs create the opening with a molecular size limit; they enhance the permeation of 150 kDa IgG mAb across the BBB but not 220 kDa fibronectin [119]. The duration time of the BBB opening by BBBM was short and the brain deposition was dependent on the size of the delivered molecule. Therefore, it limits the penetration of unwanted proteins in the blood from entering the brain. However, further safety assessment may be necessary through dose escalation studies conducted over extended periods of time. Overall, these findings highlight the potential of BBBM peptides as a promising strategy for enhancing the delivery of therapeutic agents across the BBB; however, further research is needed to fully evaluate their therapeutic impact and long-term safety.

5.5. Enhancing Antibody Retention

IgG mAbs have been observed to undergo rapid efflux after delivery into the CNS [1,2,3]. To increase the brain exposure of mAbs, one potential approach is to improve their retention once delivered. Although there has been limited scientific exploration of brain retention approaches for mAbs, one group has demonstrated that mAb binding to neural molecules within the CNS matrix can significantly enhance brain exposure [122]. In this study, the brain exposure of anti-MOG mAb targeting myelin oligodendrocyte glycoprotein (MOG), which is a brain-specific target, was compared to anti-TfR mAbs (known to cross the BBB through RMT) and a non-targeting control mAb. While the anti-TfR mAb exhibited higher brain concentrations at shorter time periods (4 days), the anti-MOG mAb demonstrated a significantly higher brain concentration as well as a longer brain exposure (10 days) compared to control mAbs. This finding can be explained by the fact that while the anti-TfR mAb rapidly accumulates in the brain, it is rapidly cleared from systemic circulation due to the widespread distribution of TfR throughout the body. In contrast, the anti-MOG mAb does not accumulate rapidly in the brain due to the restrictive CNS barriers. However, it has a much longer plasma half-life and binds strongly to its neuronal target due to its retention upon binding to target MOG protein in the brain. This target engagement allows the small amounts of mAb that access the brain from the systemic circulation to evade efflux and accumulate over time. These results highlight the potential for enhancing brain exposure by increasing mAb retention as a promising avenue for mAb treatment of brain disorders.

5.6. Brain Delivery Using Nanoparticles

Various nanoparticles have been developed for brain delivery of small drugs and macromolecules (e.g., mAbs) [123,124,125], including extracellular vesicles (EVs) [126], solid lipid nanoparticles [127], exosomes [128,129,130], nanobubbles [131,132], nanocages [133], leukocyte biomimetic nanoparticles [124], and recombinant adeno-associated viruses (rAAVs) [134,135,136]; however, these methods have not yet been successfully utilized in the clinic for delivering mAbs into the brain. Nonetheless, these methods could help in delivering mAbs as therapeutic and diagnostic agents for brain diseases.

5.7. Intranasal Brain Delivery of Proteins and Peptides

Intranasal brain delivery method has been explored to deliver peptides (e.g., oxytocin) and proteins (e.g., insulin) to the brain and some of them have reached clinical trials for treating neurodegenerative diseases (e.g., Alzheimer’s disease, autism spectrum disorder (ASD)) [137]. Nasal delivery of peptides has been shown to be more effective than IV and intraperitoneal (IP) administrations because it avoids peptide degradation in the blood [138,139,140]. The delivered molecules have to cross the nasal epithelial layer and cribriform plate for diffusion to the olfactory bulb as well as the trigeminal nerve; thus, several intranasal delivery enhancers were investigated such as tight junction disruptors (i.e., carnitines and ultrasound), CPP, receptor-mediated transport, and nanoparticles [138,139]. Although some of these methods have been approved or are undergoing clinical trials, many of these are still under investigation in the preclinical setting. If successful, these methods will help to treat patients with CNS disorders.

6. Conclusions

The progress in developing mAb therapeutics for brain disorders has been slow due to their limited CNS exposure and potential safety concerns with increasing permeation across CNS barriers. Understanding the potential mAb uptake mechanisms can give insight into potential delivery strategies for increasing mAb penetration across the BBB. Many methods have focused on this idea and have shown promise in safely facilitating this delivery. Additionally, knowledge of mAb clearance from the brain also aids in efforts to improve the exposure of antibodies. While many methods have been explored and shown promise for enhancing mAb brain exposure, there has been limited success in utilizing these methods in patients with CNS diseases that resulted in FDA approvals. Therefore, there is still a current need for expanding research and development in this research area.

Author Contributions

K.S. and T.J.S. contributed to the conceptualization, outline, flow, literature interpretation, and writing of this review article. All authors have read and agreed to the published version of the manuscript.

Funding

This study was funded by PhRMA Foundation for the Predoctoral Fellowship in Drug Delivery (PhRMA 1002407) and National Institutes of Health (R01-AG071682).

Acknowledgments

We would like to thank the PhRMA Foundation for the Predoctoral Fellowship in Drug Delivery provided to K.S. T.J.S. acknowledges the support from R01-AG071682, the National Institute on Aging (NIA), NIH.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Bergman, I.; Burckart, G.J.; Pohl, C.R.; Venkataramanan, R.; Barmada, M.A.; Griffin, J.A.; Cheung, N.K. Pharmacokinetics of IgG and IgM anti-ganglioside antibodies in rats and monkeys after intrathecal administration. J. Pharmacol. Exp. Ther. 1998, 284, 111–115. [Google Scholar] [PubMed]
  2. Noguchi, Y.; Kato, M.; Ozeki, K.; Ishigai, M. Pharmacokinetics of an intracerebroventricularly administered antibody in rats. mAbs 2017, 9, 1210–1215. [Google Scholar] [CrossRef] [PubMed]
  3. Kemshead, J.T.; Hopkins, K.; Pizer, B.; Papanastassiou, V.; Coakham, H.; Bullimore, J.; Chandler, C. Dose escalation with repeated intrathecal injections of 131I-labelled MAbs for the treatment of central nervous system malignancies. Br. J. Cancer 1998, 77, 2324–2330. [Google Scholar] [CrossRef] [PubMed]
  4. Cummings, J. Anti-Amyloid Monoclonal Antibodies are Transformative Treatments that Redefine Alzheimer's Disease Therapeutics. Drugs 2023, 83, 569–576. [Google Scholar] [CrossRef] [PubMed]
  5. Gandy, S.; Ehrlich, M.E. Moving the Needle on Alzheimer's Disease with an Anti-Oligomer Antibody. N. Engl. J. Med. 2023, 388, 80–81. [Google Scholar] [CrossRef] [PubMed]
  6. Schroeter, S.; Khan, K.; Barbour, R.; Doan, M.; Chen, M.; Guido, T.; Gill, D.; Basi, G.; Schenk, D.; Seubert, P.; et al. Immunotherapy reduces vascular amyloid-beta in PDAPP mice. J. Neurosci. 2008, 28, 6787–6793. [Google Scholar] [CrossRef] [PubMed]
  7. Armulik, A.; Genove, G.; Betsholtz, C. Pericytes: Developmental, physiological, and pathological perspectives, problems, and promises. Dev. Cell 2011, 21, 193–215. [Google Scholar] [CrossRef] [PubMed]
  8. Abbott, N.J.; Ronnback, L.; Hansson, E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat. Rev. Neurosci. 2006, 7, 41–53. [Google Scholar] [CrossRef]
  9. Kadry, H.; Noorani, B.; Cucullo, L. A blood-brain barrier overview on structure, function, impairment, and biomarkers of integrity. Fluids Barriers CNS 2020, 17, 69. [Google Scholar] [CrossRef]
  10. Pardridge, W.M. Blood-brain barrier delivery. Drug Discov Today 2007, 12, 54–61. [Google Scholar] [CrossRef]
  11. Pulgar, V.M. Transcytosis to Cross the Blood Brain Barrier, New Advancements and Challenges. Front. Neurosci. 2018, 12, 1019. [Google Scholar] [CrossRef] [PubMed]
  12. Pardridge, W.M. A Historical Review of Brain Drug Delivery. Pharmaceutics 2022, 14, 1283. [Google Scholar] [CrossRef]
  13. Spector, R.; Keep, R.F.; Robert Snodgrass, S.; Smith, Q.R.; Johanson, C.E. A balanced view of choroid plexus structure and function: Focus on adult humans. Exp. Neurol. 2015, 267, 78–86. [Google Scholar] [CrossRef]
  14. Chang, H.Y.; Morrow, K.; Bonacquisti, E.; Zhang, W.; Shah, D.K. Antibody pharmacokinetics in rat brain determined using microdialysis. mAbs 2018, 10, 843–853. [Google Scholar] [CrossRef] [PubMed]
  15. Abuqayyas, L.; Balthasar, J.P. Investigation of the role of FcgammaR and FcRn in mAb distribution to the brain. Mol. Pharm. 2013, 10, 1505–1513. [Google Scholar] [CrossRef]
  16. Garg, A.; Balthasar, J.P. Investigation of the influence of FcRn on the distribution of IgG to the brain. AAPS J. 2009, 11, 553–557. [Google Scholar] [CrossRef]
  17. Bard, F.; Fox, M.; Friedrich, S.; Seubert, P.; Schenk, D.; Kinney, G.G.; Yednock, T. Sustained levels of antibodies against Abeta in amyloid-rich regions of the CNS following intravenous dosing in human APP transgenic mice. Exp. Neurol. 2012, 238, 38–43. [Google Scholar] [CrossRef]
  18. Bohrmann, B.; Baumann, K.; Benz, J.; Gerber, F.; Huber, W.; Knoflach, F.; Messer, J.; Oroszlan, K.; Rauchenberger, R.; Richter, W.F.; et al. Gantenerumab: A novel human anti-Abeta antibody demonstrates sustained cerebral amyloid-beta binding and elicits cell-mediated removal of human amyloid-beta. J. Alzheimers Dis. 2012, 28, 49–69. [Google Scholar] [CrossRef]
  19. Antibodies in late-stage clinical studies. Available online: https://www.antibodysociety.org/antibodies-in-late-stage-clinical-studies/ (accessed on 12 July 2023).
  20. Antibody therapeutics approved or in regulatory review in the EU or US. Available online: https://www.antibodysociety.org/resources/approved-antibodies/ (accessed on 12 July 2023).
  21. Cavaco, M.; Gaspar, D.; Arb Castanho, M.; Neves, V. Antibodies for the Treatment of Brain Metastases, a Dream or a Reality? Pharmaceutics 2020, 12, 62. [Google Scholar] [CrossRef]
  22. Selewski, D.T.; Shah, G.V.; Segal, B.M.; Rajdev, P.A.; Mukherji, S.K. Natalizumab (Tysabri). AJNR Am. J. Neuroradiol. 2010, 31, 1588–1590. [Google Scholar] [CrossRef] [PubMed]
  23. Withington, C.G.; Turner, R.S. Amyloid-Related Imaging Abnormalities With Anti-amyloid Antibodies for the Treatment of Dementia Due to Alzheimer’s Disease. Front. Neurol. 2022, 13, 862369. [Google Scholar] [CrossRef]
  24. Kouhi, A.; Pachipulusu, V.; Kapenstein, T.; Hu, P.; Epstein, A.L.; Khawli, L.A. Brain Disposition of Antibody-Based Therapeutics: Dogma, Approaches and Perspectives. Int. J. Mol. Sci. 2021, 22, 6442. [Google Scholar] [CrossRef] [PubMed]
  25. Ineichen, B.V.; Plattner, P.S.; Good, N.; Martin, R.; Linnebank, M.; Schwab, M.E. Nogo-A Antibodies for Progressive Multiple Sclerosis. CNS Drugs 2017, 31, 187–198. [Google Scholar] [CrossRef] [PubMed]
  26. Ruggieri, S.; Tortorella, C.; Gasperini, C. Anti lingo 1 (opicinumab) a new monoclonal antibody tested in relapsing remitting multiple sclerosis. Expert. Rev. Neurother. 2017, 17, 1081–1089. [Google Scholar] [CrossRef]
  27. Ciric, B.; Howe, C.L.; Paz Soldan, M.; Warrington, A.E.; Bieber, A.J.; Van Keulen, V.; Rodriguez, M.; Pease, L.R. Human monoclonal IgM antibody promotes CNS myelin repair independent of Fc function. Brain Pathol. 2003, 13, 608–616. [Google Scholar] [CrossRef] [PubMed]
  28. Fisher, T.L.; Reilly, C.A.; Winter, L.A.; Pandina, T.; Jonason, A.; Scrivens, M.; Balch, L.; Bussler, H.; Torno, S.; Seils, J.; et al. Generation and preclinical characterization of an antibody specific for SEMA4D. mAbs 2016, 8, 150–162. [Google Scholar] [CrossRef]
  29. Florian, H.; Arnold, S.E.; Bateman, R.; Braunstein, J.B.; Budur, K.; Kerwin, D.R.; Soares, H.; Wang, D.; Holtzman, D.M. BBV-8E12, A humanized anti-Tau monoclonal antibody for treating early Alzheimer’s disease: Updated design and baseline characteristics of a Phase 2 study. Alzheimer’s Dementia 2019, 15, 251–252. [Google Scholar] [CrossRef]
  30. Rubenstein, J.L.; Combs, D.; Rosenberg, J.; Levy, A.; McDermott, M.; Damon, L.; Ignoffo, R.; Aldape, K.; Shen, A.; Lee, D.; et al. Rituximab therapy for CNS lymphomas: Targeting the leptomeningeal compartment. Blood 2003, 101, 466–468. [Google Scholar] [CrossRef]
  31. Pardridge, W.M. CSF, blood-brain barrier, and brain drug delivery. Expert. Opin. Drug Deliv. 2016, 13, 963–975. [Google Scholar] [CrossRef]
  32. Reiber, H. Proteins in cerebrospinal fluid and blood: Barriers, CSF flow rate and source-related dynamics. Restor. Neurol. Neurosci. 2003, 21, 79–96. [Google Scholar]
  33. Van De Vyver, A.J.; Walz, A.C.; Heins, M.S.; Abdolzade-Bavil, A.; Kraft, T.E.; Waldhauer, I.; Otteneder, M.B. Investigating brain uptake of a non-targeting monoclonal antibody after intravenous and intracerebroventricular administration. Front. Pharmacol. 2022, 13, 958543. [Google Scholar] [CrossRef]
  34. Ruano-Salguero, J.S.; Lee, K.H. Antibody transcytosis across brain endothelial-like cells occurs nonspecifically and independent of FcRn. Sci. Rep. 2020, 10, 3685. [Google Scholar] [CrossRef]
  35. Yu, Y.J.; Watts, R.J. Developing therapeutic antibodies for neurodegenerative disease. Neurotherapeutics 2013, 10, 459–472. [Google Scholar] [CrossRef]
  36. Mantle, J.L.; Lee, K.H. Immunoglobulin G transport increases in an in vitro blood-brain barrier model with amyloid-beta and with neuroinflammatory cytokines. Biotechnol. Bioeng. 2019, 116, 1752–1761. [Google Scholar] [CrossRef] [PubMed]
  37. Atwal, J.K.; Chen, Y.; Chiu, C.; Mortensen, D.L.; Meilandt, W.J.; Liu, Y.; Heise, C.E.; Hoyte, K.; Luk, W.; Lu, Y.; et al. A therapeutic antibody targeting BACE1 inhibits amyloid-beta production in vivo. Sci. Transl. Med. 2011, 3, 84ra43. [Google Scholar] [CrossRef] [PubMed]
  38. Triguero, D.; Buciak, J.B.; Yang, J.; Pardridge, W.M. Blood-brain barrier transport of cationized immunoglobulin G: Enhanced delivery compared to native protein. Proc. Natl. Acad. Sci. USA 1989, 86, 4761–4765. [Google Scholar] [CrossRef] [PubMed]
  39. Kumagai, A.K.; Eisenberg, J.B.; Pardridge, W.M. Absorptive-mediated endocytosis of cationized albumin and a beta-endorphin-cationized albumin chimeric peptide by isolated brain capillaries. Model system of blood-brain barrier transport. J. Biol. Chem. 1987, 262, 15214–15219. [Google Scholar] [CrossRef]
  40. Zhang, Y.; Pardridge, W.M. Mediated efflux of IgG molecules from brain to blood across the blood-brain barrier. J. Neuroimmunol. 2001, 114, 168–172. [Google Scholar] [CrossRef]
  41. Wolak, D.J.; Pizzo, M.E.; Thorne, R.G. Probing the extracellular diffusion of antibodies in brain using in vivo integrative optical imaging and ex vivo fluorescence imaging. J. Control Release 2015, 197, 78–86. [Google Scholar] [CrossRef] [PubMed]
  42. Roopenian, D.C.; Akilesh, S. FcRn: The neonatal Fc receptor comes of age. Nat. Rev. Immunol. 2007, 7, 715–725. [Google Scholar] [CrossRef]
  43. Schlachetzki, F.; Zhu, C.; Pardridge, W.M. Expression of the neonatal Fc receptor (FcRn) at the blood-brain barrier. J. Neurochem. 2002, 81, 203–206. [Google Scholar] [CrossRef] [PubMed]
  44. Yip, V.; Palma, E.; Tesar, D.B.; Mundo, E.E.; Bumbaca, D.; Torres, E.K.; Reyes, N.A.; Shen, B.Q.; Fielder, P.J.; Prabhu, S.; et al. Quantitative cumulative biodistribution of antibodies in mice: Effect of modulating binding affinity to the neonatal Fc receptor. MAbs 2014, 6, 689–696. [Google Scholar] [CrossRef] [PubMed]
  45. Boado, R.J.; Zhang, Y.; Zhang, Y.; Xia, C.F.; Pardridge, W.M. Fusion antibody for Alzheimer’s disease with bidirectional transport across the blood-brain barrier and abeta fibril disaggregation. Bioconjug Chem. 2007, 18, 447–455. [Google Scholar] [CrossRef]
  46. Cooper, P.R.; Ciambrone, G.J.; Kliwinski, C.M.; Maze, E.; Johnson, L.; Li, Q.; Feng, Y.; Hornby, P.J. Efflux of monoclonal antibodies from rat brain by neonatal Fc receptor, FcRn. Brain Res. 2013, 1534, 13–21. [Google Scholar] [CrossRef]
  47. Deane, R.; Sagare, A.; Hamm, K.; Parisi, M.; LaRue, B.; Guo, H.; Wu, Z.; Holtzman, D.M.; Zlokovic, B.V. IgG-assisted age-dependent clearance of Alzheimer's amyloid beta peptide by the blood-brain barrier neonatal Fc receptor. J. Neurosci. 2005, 25, 11495–11503. [Google Scholar] [CrossRef] [PubMed]
  48. Aukland, K.; Reed, R.K. Interstitial-lymphatic mechanisms in the control of extracellular fluid volume. Physiol. Rev. 1993, 73, 1–78. [Google Scholar] [CrossRef]
  49. Iliff, J.J.; Wang, M.; Liao, Y.; Plogg, B.A.; Peng, W.; Gundersen, G.A.; Benveniste, H.; Vates, G.E.; Deane, R.; Goldman, S.A.; et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci. Transl. Med. 2012, 4, 147ra111. [Google Scholar] [CrossRef]
  50. Ding, Z.; Fan, X.; Zhang, Y.; Yao, M.; Wang, G.; Dong, Y.; Liu, J.; Song, W. The glymphatic system: A new perspective on brain diseases. Front. Aging Neurosci. 2023, 15, 1179988. [Google Scholar] [CrossRef]
  51. Yang, L.; Kress, B.T.; Weber, H.J.; Thiyagarajan, M.; Wang, B.; Deane, R.; Benveniste, H.; Iliff, J.J.; Nedergaard, M. Evaluating glymphatic pathway function utilizing clinically relevant intrathecal infusion of CSF tracer. J. Transl. Med. 2013, 11, 107. [Google Scholar] [CrossRef]
  52. Kress, B.T.; Iliff, J.J.; Xia, M.; Wang, M.; Wei, H.S.; Zeppenfeld, D.; Xie, L.; Kang, H.; Xu, Q.; Liew, J.A.; et al. Impairment of paravascular clearance pathways in the aging brain. Ann. Neurol. 2014, 76, 845–861. [Google Scholar] [CrossRef]
  53. Takano, K.; Yamada, M. Contrast-enhanced magnetic resonance imaging evidence for the role of astrocytic aquaporin-4 water channels in glymphatic influx and interstitial solute transport. Magn. Reson. Imaging 2020, 71, 11–16. [Google Scholar] [CrossRef] [PubMed]
  54. Cserr, H.F.; Cooper, D.N.; Suri, P.K.; Patlak, C.S. Efflux of radiolabeled polyethylene glycols and albumin from rat brain. Am. J. Physiol. 1981, 240, F319–F328. [Google Scholar] [CrossRef] [PubMed]
  55. Gomolka, R.S.; Hablitz, L.M.; Mestre, H.; Giannetto, M.; Du, T.; Hauglund, N.L.; Xie, L.; Peng, W.; Martinez, P.M.; Nedergaard, M.; et al. Loss of aquaporin-4 results in glymphatic system dysfunction via brain-wide interstitial fluid stagnation. Elife 2023, 12, e82232. [Google Scholar] [CrossRef] [PubMed]
  56. Nicholson, C.; Sykova, E. Extracellular space structure revealed by diffusion analysis. Trends Neurosci. 1998, 21, 207–215. [Google Scholar] [CrossRef] [PubMed]
  57. Begley, D.J. Brain superhighways. Sci. Transl. Med. 2012, 4, 147fs129. [Google Scholar] [CrossRef]
  58. Verkman, A.S.; Tradtrantip, L.; Smith, A.J.; Yao, X. Aquaporin Water Channels and Hydrocephalus. Pediatr. Neurosurg. 2017, 52, 409–416. [Google Scholar] [CrossRef]
  59. Pizzo, M.E.; Wolak, D.J.; Kumar, N.N.; Brunette, E.; Brunnquell, C.L.; Hannocks, M.J.; Abbott, N.J.; Meyerand, M.E.; Sorokin, L.; Stanimirovic, D.B.; et al. Intrathecal antibody distribution in the rat brain: Surface diffusion, perivascular transport and osmotic enhancement of delivery. J. Physiol. 2018, 596, 445–475. [Google Scholar] [CrossRef]
  60. Pardridge, W.M. Molecular Trojan horses for blood-brain barrier drug delivery. Curr. Opin. Pharmacol. 2006, 6, 494–500. [Google Scholar] [CrossRef]
  61. Pardridge, W.M.; Buciak, J.L.; Friden, P.M. Selective transport of an anti-transferrin receptor antibody through the blood-brain barrier in vivo. J. Pharmacol. Exp. Ther. 1991, 259, 66–70. [Google Scholar] [PubMed]
  62. Friden, P.M.; Walus, L.R.; Musso, G.F.; Taylor, M.A.; Malfroy, B.; Starzyk, R.M. Anti-transferrin receptor antibody and antibody-drug conjugates cross the blood-brain barrier. Proc. Natl. Acad. Sci. USA 1991, 88, 4771–4775. [Google Scholar] [CrossRef]
  63. Roth, R.A.; Cassell, D.J.; Wong, K.Y.; Maddux, B.A.; Goldfine, I.D. Monoclonal antibodies to the human insulin receptor block insulin binding and inhibit insulin action. Proc. Natl. Acad. Sci. USA 1982, 79, 7312–7316. [Google Scholar] [CrossRef]
  64. Bickel, U.; Yoshikawa, T.; Landaw, E.M.; Faull, K.F.; Pardridge, W.M. Pharmacologic effects in vivo in brain by vector-mediated peptide drug delivery. Proc. Natl. Acad. Sci. USA 1993, 90, 2618–2622. [Google Scholar] [CrossRef]
  65. Friden, P.M.; Walus, L.R.; Watson, P.; Doctrow, S.R.; Kozarich, J.W.; Backman, C.; Bergman, H.; Hoffer, B.; Bloom, F.; Granholm, A.C. Blood-brain barrier penetration and in vivo activity of an NGF conjugate. Science 1993, 259, 373–377. [Google Scholar] [CrossRef]
  66. Wu, D.; Yang, J.; Pardridge, W.M. Drug targeting of a peptide radiopharmaceutical through the primate blood-brain barrier in vivo with a monoclonal antibody to the human insulin receptor. J. Clin. Invest. 1997, 100, 1804–1812. [Google Scholar] [CrossRef]
  67. Gosk, S.; Vermehren, C.; Storm, G.; Moos, T. Targeting anti-transferrin receptor antibody (OX26) and OX26-conjugated liposomes to brain capillary endothelial cells using in situ perfusion. J. Cereb. Blood Flow. Metab. 2004, 24, 1193–1204. [Google Scholar] [CrossRef] [PubMed]
  68. Moos, T.; Morgan, E.H. Restricted transport of anti-transferrin receptor antibody (OX26) through the blood-brain barrier in the rat. J. Neurochem. 2001, 79, 119–129. [Google Scholar] [CrossRef] [PubMed]
  69. Chang, H.Y.; Wu, S.; Li, Y.; Zhang, W.; Burrell, M.; Webster, C.I.; Shah, D.K. Brain pharmacokinetics of anti-transferrin receptor antibody affinity variants in rats determined using microdialysis. mAbs 2021, 13, 1874121. [Google Scholar] [CrossRef] [PubMed]
  70. Yu, Y.J.; Zhang, Y.; Kenrick, M.; Hoyte, K.; Luk, W.; Lu, Y.; Atwal, J.; Elliott, J.M.; Prabhu, S.; Watts, R.J.; et al. Boosting brain uptake of a therapeutic antibody by reducing its affinity for a transcytosis target. Sci. Transl. Med. 2011, 3, 84ra44. [Google Scholar] [CrossRef]
  71. Niewoehner, J.; Bohrmann, B.; Collin, L.; Urich, E.; Sade, H.; Maier, P.; Rueger, P.; Stracke, J.O.; Lau, W.; Tissot, A.C.; et al. Increased brain penetration and potency of a therapeutic antibody using a monovalent molecular shuttle. Neuron 2014, 81, 49–60. [Google Scholar] [CrossRef]
  72. Haqqani, A.S.; Thom, G.; Burrell, M.; Delaney, C.E.; Brunette, E.; Baumann, E.; Sodja, C.; Jezierski, A.; Webster, C.; Stanimirovic, D.B. 2018. Intracellular sorting and transcytosis of the rat transferrin receptor antibody OX26 across the blood-brain barrier in vitro is dependent on its binding affinity. J. Neurochem. 2018, 146, 735–752. [Google Scholar] [CrossRef] [PubMed]
  73. Boado, R.J.; Hui, E.K.; Lu, J.Z.; Pardridge, W.M. IgG-enzyme fusion protein: Pharmacokinetics and anti-drug antibody response in rhesus monkeys. Bioconjug Chem. 2013, 24, 97–104. [Google Scholar] [CrossRef] [PubMed]
  74. Giugliani, R.; Nestrasil, I.; Chen, S.; Pardridge, W.M.; Rioux, P. Intravenous Infusion of Iduronidase-IgG and Its Impact on the Central Nervous System in Children with Hurler Syndrome. Mol. Genet. Metab. 2017, 120, S55–S56. [Google Scholar] [CrossRef]
  75. Leoh, L.S.; Daniels-Wells, T.R.; Martinez-Maza, O.; Penichet, M.L. Insights into the effector functions of human IgG3 in the context of an antibody targeting transferrin receptor 1. Mol. Immunol. 2015, 67 Pt B, 407–415. [Google Scholar] [CrossRef]
  76. Okuyama, T.; Eto, Y.; Sakai, N.; Minami, K.; Yamamoto, T.; Sonoda, H.; Yamaoka, M.; Tachibana, K.; Hirato, T.; Sato, Y. Iduronate-2-Sulfatase with Anti-human Transferrin Receptor Antibody for Neuropathic Mucopolysaccharidosis II: A Phase 1/2 Trial. Mol. Ther. 2019, 27, 456–464. [Google Scholar] [CrossRef] [PubMed]
  77. Okuyama, T.; Eto, Y.; Sakai, N.; Nakamura, K.; Yamamoto, T.; Yamaoka, M.; Ikeda, T.; So, S.; Tanizawa, K.; Sonoda, H.; et al. A Phase 2/3 Trial of Pabinafusp Alfa, IDS Fused with Anti-Human Transferrin Receptor Antibody, Targeting Neurodegeneration in MPS-II. Mol. Ther. 2021, 29, 671–679. [Google Scholar] [CrossRef] [PubMed]
  78. Giugliani, R.; Martins, A.M.; So, S.; Yamamoto, T.; Yamaoka, M.; Ikeda, T.; Tanizawa, K.; Sonoda, H.; Schmidt, M.; Sato, Y. Iduronate-2-sulfatase fused with anti-hTfR antibody, pabinafusp alfa, for MPS-II: A phase 2 trial in Brazil. Mol. Ther. 2021, 29, 2378–2386. [Google Scholar] [CrossRef]
  79. Kullic, L.; Vogt, A.; Alcarez, F.; Barrington, P.; Marchesi, M.; Svoboda, H. Brain Shuttle AD: Investigationg Safety, Tolerability, and PK/PD of RG6102 in Prodromal/Mild-to-Moderate AD. J. Neurol. Neurosurg. Psychiatry 2020, 27, 2019–2020. [Google Scholar]
  80. Weber, F.; Bohrmann, B.; Niewoehner, J.; Fischer, J.A.A.; Rueger, P.; Tiefenthaler, G.; Moelleken, J.; Bujotzek, A.; Brady, K.; Singer, T.; et al. Brain Shuttle Antibody for Alzheimer’s Disease with Attenuated Peripheral Effector Function due to an Inverted Binding Mode. Cell Rep. 2018, 22, 149–162. [Google Scholar] [CrossRef]
  81. Rapoport, S.I. Effect of concentrated solutions on blood-brain barrier. Am. J. Physiol. 1970, 219, 270–274. [Google Scholar] [CrossRef]
  82. Rapoport, S.I.; Hori, M.; Klatzo, I. Testing of a hypothesis for osmotic opening of the blood-brain barrier. Am. J. Physiol. 1972, 223, 323–331. [Google Scholar] [CrossRef]
  83. Mayhan, W.G.; Heistad, D.D. Permeability of blood-brain barrier to various sized molecules. Am. J. Physiol. 1985, 248 Pt 2, H712–H718. [Google Scholar] [CrossRef] [PubMed]
  84. Neuwelt, E.A.; Barnett, P.A.; Hellstrom, I.; Hellstrom, K.E.; Beaumier, P.; McCormick, C.I.; Weigel, R.M. Delivery of melanoma-associated immunoglobulin monoclonal antibody and Fab fragments to normal brain utilizing osmotic blood-brain barrier disruption. Cancer Res. 1988, 48, 4725–4729. [Google Scholar] [PubMed]
  85. Neuwelt, E.A.; Minna, J.; Frenkel, E.; Barnett, P.A.; McCormick, C.I. Osmotic blood-brain barrier opening to IgM monoclonal antibody in the rat. Am. J. Physiol. 1986, 250 Pt 2, R875–R883. [Google Scholar] [CrossRef] [PubMed]
  86. Bullard, D.E.; Bourdon, M.; Bigner, D.D. Comparison of various methods for delivering radiolabeled monoclonal antibody to normal rat brain. J. Neurosurg. 1984, 61, 901–911. [Google Scholar] [CrossRef] [PubMed]
  87. Hicks, J.T.; Albrecht, P.; Rapoport, S.I. Entry of neutralizing antibody to measles into brain and cerebrospinal fluid of immunized monkeys after osmotic opening of the blood-brain barrier. Exp. Neurol. 1976, 53, 768–779. [Google Scholar] [CrossRef]
  88. Neuwelt, E.A.; Barnett, P.A.; McCormick, C.I.; Frenkel, E.P.; Minna, J.D. Osmotic blood-brain barrier modification: Monoclonal antibody, albumin, and methotrexate delivery to cerebrospinal fluid and brain. Neurosurgery 1985, 17, 419–423. [Google Scholar] [CrossRef]
  89. Neuwelt, E.A.; Specht, H.D.; Barnett, P.A.; Dahlborg, S.A.; Miley, A.; Larson, S.M.; Brown, P.; Eckerman, K.F.; Hellstrom, K.E.; Hellstrom, I. Increased delivery of tumor-specific monoclonal antibodies to brain after osmotic blood-brain barrier modification in patients with melanoma metastatic to the central nervous system. Neurosurgery 1987, 20, 885–895. [Google Scholar] [CrossRef]
  90. Neuwelt, E.A.; Specht, H.D.; Hill, S.A. Permeability of human brain tumor to 99mTc-gluco-heptonate and 99mTc-albumin. Implications for monoclonal antibody therapy. J. Neurosurg. 1986, 65, 194–198. [Google Scholar] [CrossRef]
  91. Remsen, L.G.; Trail, P.A.; Hellstrom, I.; Hellstrom, K.E.; Neuwelt, E.A. Enhanced delivery improves the efficacy of a tumor-specific doxorubicin immunoconjugate in a human brain tumor xenograft model. Neurosurgery 2000, 46, 704–709. [Google Scholar] [CrossRef]
  92. Muldoon, L.L.; Neuwelt, E.A. BR96-DOX immunoconjugate targeting of chemotherapy in brain tumor models. J. Neurooncol 2003, 65, 49–62. [Google Scholar] [CrossRef]
  93. Nadal, A.; Fuentes, E.; Pastor, J.; McNaughton, P.A. Plasma albumin is a potent trigger of calcium signals and DNA synthesis in astrocytes. Proc. Natl. Acad. Sci. USA 1995, 92, 1426–1430. [Google Scholar] [CrossRef] [PubMed]
  94. Petersen, M.A.; Ryu, J.K.; Chang, K.J.; Etxeberria, A.; Bardehle, S.; Mendiola, A.S.; Kamau-Devers, W.; Fancy, S.P.J.; Thor, A.; Bushong, E.A.; et al. Fibrinogen Activates BMP Signaling in Oligodendrocyte Progenitor Cells and Inhibits Remyelination after Vascular Damage. Neuron 2017, 96, 1003–1012.e1007. [Google Scholar] [CrossRef] [PubMed]
  95. Salahuddin, T.S.; Johansson, B.B.; Kalimo, H.; Olsson, Y. Structural changes in the rat brain after carotid infusions of hyperosmolar solutions. An electron microscopic study. Acta Neuropathol. 1988, 77, 5–13. [Google Scholar] [CrossRef] [PubMed]
  96. Burks, S.R.; Kersch, C.N.; Witko, J.A.; Pagel, M.A.; Sundby, M.; Muldoon, L.L.; Neuwelt, E.A.; Frank, J.A. Blood-brain barrier opening by intracarotid artery hyperosmolar mannitol induces sterile inflammatory and innate immune responses. Proc. Natl. Acad. Sci. USA 2021, 118, e2021915118. [Google Scholar] [CrossRef]
  97. Lossinsky, A.S.; Vorbrodt, A.W.; Wisniewski, H.M. Scanning and transmission electron microscopic studies of microvascular pathology in the osmotically impaired blood-brain barrier. J. Neurocytol. 1995, 24, 795–806. [Google Scholar] [CrossRef]
  98. Warwick, R.; Pond, J. Trackless Lesions in Nervous Tissues Produced by High Intensity Focused Ultrasound (High-Frequency Mechanical Waves). J. Anat. 1968, 102, 387–405. [Google Scholar]
  99. Vykhodtseva, N.I.; Hynynen, K.; Damianou, C. Histologic effects of high intensity pulsed ultrasound exposure with subharmonic emission in rabbit brain in vivo. Ultrasound Med. Biol. 1995, 21, 969–979. [Google Scholar] [CrossRef]
  100. Hynynen, K.; McDannold, N.; Vykhodtseva, N.; Jolesz, F.A. Noninvasive MR imaging-guided focal opening of the blood-brain barrier in rabbits. Radiology 2001, 220, 640–646. [Google Scholar] [CrossRef] [PubMed]
  101. Choi, J.J.; Wang, S.; Tung, Y.S.; Morrison, B., 3rd; Konofagou, E.E. Molecules of various pharmacologically-relevant sizes can cross the ultrasound-induced blood-brain barrier opening in vivo. Ultrasound Med. Biol. 2010, 36, 58–67. [Google Scholar] [CrossRef]
  102. Chen, H.; Konofagou, E.E. The size of blood-brain barrier opening induced by focused ultrasound is dictated by the acoustic pressure. J. Cereb. Blood Flow. Metab. 2014, 34, 1197–1204. [Google Scholar] [CrossRef]
  103. Kinoshita, M.; McDannold, N.; Jolesz, F.A.; Hynynen, K. Noninvasive localized delivery of Herceptin to the mouse brain by MRI-guided focused ultrasound-induced blood-brain barrier disruption. Proc. Natl. Acad. Sci. USA 2006, 103, 11719–11723. [Google Scholar] [CrossRef]
  104. Kinoshita, M.; McDannold, N.; Jolesz, F.A.; Hynynen, K. Targeted delivery of antibodies through the blood-brain barrier by MRI-guided focused ultrasound. Biochem. Biophys. Res. Commun. 2006, 340, 1085–1090. [Google Scholar] [CrossRef] [PubMed]
  105. Sun, T.; Shi, Q.; Zhang, Y.; Power, C.; Hoesch, C.; Antonelli, S.; Schroeder, M.K.; Caldarone, B.J.; Taudte, N.; Schenk, M.; et al. Focused ultrasound with anti-pGlu3 Abeta enhances efficacy in Alzheimer's disease-like mice via recruitment of peripheral immune cells. J. Control Release 2021, 336, 443–456. [Google Scholar] [CrossRef]
  106. Mainprize, T.; Lipsman, N.; Huang, Y.; Meng, Y.; Bethune, A.; Ironside, S.; Heyn, C.; Alkins, R.; Trudeau, M.; Sahgal, A.; et al. Blood-Brain Barrier Opening in Primary Brain Tumors with Non-invasive MR-Guided Focused Ultrasound: A Clinical Safety and Feasibility Study. Sci. Rep. 2019, 9, 321. [Google Scholar] [CrossRef]
  107. Lipsman, N.; Meng, Y.; Bethune, A.J.; Huang, Y.; Lam, B.; Masellis, M.; Herrmann, N.; Heyn, C.; Aubert, I.; Boutet, A.; et al. Blood-brain barrier opening in Alzheimer's disease using MR-guided focused ultrasound. Nat. Commun. 2018, 9, 2336. [Google Scholar] [CrossRef] [PubMed]
  108. Lutz, K.L.; Siahaan, T.J. Modulation of the cellular junction protein E-cadherin in bovine brain microvessel endothelial cells by cadherin peptides. Drug Deliv. 1997, 4, 187–193. [Google Scholar] [CrossRef]
  109. Makagiansar, I.T.; Avery, M.; Hu, Y.; Audus, K.L.; Siahaan, T.J. Improving the selectivity of HAV-peptides in modulating E-cadherin-E-cadherin interactions in the intercellular junction of MDCK cell monolayers. Pharm. Res. 2001, 18, 446–453. [Google Scholar] [CrossRef]
  110. Sinaga, E.; Jois, S.D.; Avery, M.; Makagiansar, I.T.; Tambunan, U.S.; Audus, K.L.; Siahaan, T.J. Increasing paracellular porosity by E-cadherin peptides: Discovery of bulge and groove regions in the EC1-domain of E-cadherin. Pharm. Res. 2002, 19, 1170–1179. [Google Scholar] [CrossRef] [PubMed]
  111. Kiptoo, P.; Sinaga, E.; Calcagno, A.M.; Zhao, H.; Kobayashi, N.; Tambunan, U.S.; Siahaan, T.J. Enhancement of drug absorption through the blood-brain barrier and inhibition of intercellular tight junction resealing by E-cadherin peptides. Mol. Pharm. 2011, 8, 239–249. [Google Scholar] [CrossRef]
  112. Tabanor, K.; Lee, P.; Kiptoo, P.; Choi, I.Y.; Sherry, E.B.; Eagle, C.S.; Williams, T.D.; Siahaan, T.J. Brain Delivery of Drug and MRI Contrast Agent: Detection and Quantitative Determination of Brain Deposition of CPT-Glu Using LC-MS/MS and Gd-DTPA Using Magnetic Resonance Imaging. Mol. Pharm. 2016, 13, 379–390. [Google Scholar] [CrossRef]
  113. Laksitorini, M.D.; Kiptoo, P.K.; On, N.H.; Thliveris, J.A.; Miller, D.W.; Siahaan, T.J. Modulation of intercellular junctions by cyclic-ADT peptides as a method to reversibly increase blood-brain barrier permeability. J. Pharm. Sci. 2015, 104, 1065–1075. [Google Scholar] [CrossRef]
  114. On, N.H.; Kiptoo, P.; Siahaan, T.J.; Miller, D.W. Modulation of blood-brain barrier permeability in mice using synthetic E-cadherin peptide. Mol. Pharm. 2014, 11, 974–981. [Google Scholar] [CrossRef] [PubMed]
  115. Alaofi, A.; On, N.; Kiptoo, P.; Williams, T.D.; Miller, D.W.; Siahaan, T.J. Comparison of Linear and Cyclic His-Ala-Val Peptides in Modulating the Blood-Brain Barrier Permeability: Impact on Delivery of Molecules to the Brain. J. Pharm. Sci. 2016, 105, 797–807. [Google Scholar] [CrossRef] [PubMed]
  116. Ulapane, K.R.; On, N.; Kiptoo, P.; Williams, T.D.; Miller, D.W.; Siahaan, T.J. Improving Brain Delivery of Biomolecules via BBB Modulation in Mouse and Rat: Detection using MRI, NIRF, and Mass Spectrometry. Nanotheranostics 2017, 1, 217–231. [Google Scholar] [CrossRef]
  117. Kopec, B.M.; Kiptoo, P.; Zhao, L.; Rosa-Molinar, E.; Siahaan, T.J. Noninvasive Brain Delivery and Efficacy of BDNF to Stimulate Neuroregeneration and Suppression of Disease Relapse in EAE Mice. Mol. Pharm. 2020, 17, 404–416. [Google Scholar] [CrossRef] [PubMed]
  118. Kopec, B.M.; Zhao, L.; Rosa-Molinar, E.; Siahaan, T.J. Non-invasive Brain Delivery and Efficacy of BDNF in APP/PS1 Transgenic Mice as a Model of Alzheimer's Disease. Med. Res. Arch. 2020, 8, 2043. [Google Scholar] [CrossRef]
  119. Ulapane, K.R.; Kopec, B.M.; Siahaan, T.J. In Vivo Brain Delivery and Brain Deposition of Proteins with Various Sizes. Mol. Pharm. 2019, 16, 4878–4889. [Google Scholar] [CrossRef]
  120. Ulapane, K.R.; Kopec, B.M.; Siahaan, T.J. Improving In Vivo Brain Delivery of Monoclonal Antibody Using Novel Cyclic Peptides. Pharmaceutics 2019, 11, 568. [Google Scholar] [CrossRef]
  121. Sajesh, B.V.; On, N.H.; Omar, R.; Alrushaid, S.; Kopec, B.M.; Wang, W.G.; Sun, H.D.; Lillico, R.; Lakowski, T.M.; Siahaan, T.J.; et al. Validation of Cadherin HAV6 Peptide in the Transient Modulation of the Blood-Brain Barrier for the Treatment of Brain Tumors. Pharmaceutics 2019, 11, 481. [Google Scholar] [CrossRef]
  122. Nakano, R.; Takagi-Maeda, S.; Ito, Y.; Kishimoto, S.; Osato, T.; Noguchi, K.; Kurihara-Suda, K.; Takahashi, N. A new technology for increasing therapeutic protein levels in the brain over extended periods. PLoS ONE 2019, 14, e0214404. [Google Scholar] [CrossRef]
  123. Bukhari, S.N.A. Nanotherapeutics for Alzheimer's Disease with Preclinical Evaluation and Clinical Trials: Challenges, Promises and Limitations. Curr. Drug Deliv. 2021, 19, 17–31. [Google Scholar] [CrossRef]
  124. Zinger, A.; Soriano, S.; Baudo, G.; De Rosa, E.; Taraballi, F.; Villapol, S. Biomimetic Nanoparticles as a Theranostic Tool for Traumatic Brain Injury. Adv. Funct. Mater. 2021, 31, 2100722. [Google Scholar] [CrossRef]
  125. Han, L.; Jiang, C. Evolution of blood-brain barrier in brain diseases and related systemic nanoscale brain-targeting drug delivery strategies. Acta Pharm. Sin. B 2021, 11, 2306–2325. [Google Scholar] [CrossRef]
  126. Busatto, S.; Morad, G.; Guo, P.; Moses, M.A. The role of extracellular vesicles in the physiological and pathological regulation of the blood-brain barrier. FASEB Bioadv. 2021, 3, 665–675. [Google Scholar] [CrossRef]
  127. Satapathy, M.K.; Yen, T.L.; Jan, J.S.; Tang, R.D.; Wang, J.Y.; Taliyan, R.; Yang, C.H. Solid Lipid Nanoparticles (SLNs): An Advanced Drug Delivery System Targeting Brain through, B.B.B. Pharmaceutics 2021, 13, 1183. [Google Scholar] [CrossRef] [PubMed]
  128. Jain, K.K. Nanobiotechnology-based strategies for crossing the blood-brain barrier. Nanomedicine 2012, 7, 1225–1233. [Google Scholar] [CrossRef] [PubMed]
  129. Yang, T.; Martin, P.; Fogarty, B.; Brown, A.; Schurman, K.; Phipps, R.; Yin, V.P.; Lockman, P.; Bai, S. Exosome delivered anticancer drugs across the blood-brain barrier for brain cancer therapy in Danio rerio. Pharm. Res. 2015, 32, 2003–2014. [Google Scholar] [CrossRef]
  130. Zheng, M.; Huang, M.; Ma, X.; Chen, H.; Gao, X. Harnessing Exosomes for the Development of Brain Drug Delivery Systems. Bioconjug. Chem. 2019, 30, 994–1005. [Google Scholar] [CrossRef]
  131. Lea-Banks, H.; Hynynen, K. Sub-millimetre precision of drug delivery in the brain from ultrasound-triggered nanodroplets. J. Control Release 2021, 338, 731–741. [Google Scholar] [CrossRef] [PubMed]
  132. Xie, X.; Yang, Y.; Lin, W.; Liu, H.; Liu, H.; Yang, Y.; Chen, Y.; Fu, X.; Deng, J. Cell-penetrating peptide-siRNA conjugate loaded YSA-modified nanobubbles for ultrasound triggered siRNA delivery. Colloids Surf. B Biointerfaces 2015, 136, 641–650. [Google Scholar] [CrossRef] [PubMed]
  133. Zhai, M.; Wang, Y.; Zhang, L.; Liang, M.; Fu, S.; Cui, L.; Yang, M.; Gong, W.; Li, Z.; Yu, L.; et al. Glioma targeting peptide modified apoferritin nanocage. Drug Deliv. 2018, 25, 1013–1024. [Google Scholar] [CrossRef]
  134. Albright, B.H.; Storey, C.M.; Murlidharan, G.; Castellanos Rivera, R.M.; Berry, G.E.; Madigan, V.J.; Asokan, A. Mapping the Structural Determinants Required for AAVrh.10 Transport across the Blood-Brain Barrier. Mol. Ther. 2018, 26, 510–523. [Google Scholar] [CrossRef]
  135. Agbandje-McKenna, M.; Kleinschmidt, J. AAV capsid structure and cell interactions. Methods Mol. Biol. 2011, 807, 47–92. [Google Scholar] [CrossRef] [PubMed]
  136. Madigan, V.J.; Asokan, A. Engineering AAV receptor footprints for gene therapy. Curr. Opin. Virol. 2016, 18, 89–96. [Google Scholar] [CrossRef] [PubMed]
  137. Tanaka, A.; Furubayashi, T.; Arai, M.; Inoue, D.; Kimura, S.; Kiriyama, A.; Kusamori, K.; Katsumi, H.; Yutani, R.; Sakane, T.; et al. Delivery of Oxytocin to the Brain for the Treatment of Autism Spectrum Disorder by Nasal Application. Mol. Pharm. 2018, 15, 1105–1111. [Google Scholar] [CrossRef] [PubMed]
  138. Samaridou, E.; Alonso, M.J. Nose-to-brain peptide delivery—The potential of nanotechnology. Bioorg Med. Chem. 2018, 26, 2888–2905. [Google Scholar] [CrossRef] [PubMed]
  139. Meredith, M.E.; Salameh, T.S.; Banks, W.A. Intranasal Delivery of Proteins and Peptides in the Treatment of Neurodegenerative Diseases. AAPS J. 2015, 17, 780–787. [Google Scholar] [CrossRef]
  140. Dufes, C.; Olivier, J.C.; Gaillard, F.; Gaillard, A.; Couet, W.; Muller, J.M. Brain delivery of vasoactive intestinal peptide (VIP) following nasal administration to rats. Int. J. Pharm. 2003, 255, 87–97. [Google Scholar] [CrossRef]
Jnt 04 00020 g001
Figure 1. (A) A schematic of the BBB that is composed of endothelial cells (blue) surrounded by supportive pericytes (green) and astrocytic endfeet (pink). The basement membrane (light blue) is shared between pericytes and endothelial, while perivascular spaces (yellow) are located between the basement membrane and astrocytic endfeet and are filled with CSF. AQP4 channels on astrocytic endfeet mediate water flux into PVS. (B) In the glymphatic system, fluid movement is facilitated by AQP4 channels located on astrocytic endfeet, driving convective flow from the CSF-filled periarterial spaces to the perivenous spaces. This convective flow within the brain parenchyma is believed to contribute to the clearance of waste products from the brain. Subsequently, the parenchymal waste present in the CSF is drained into the peripheral lymphatics through the perivenous spaces.
Figure 1. (A) A schematic of the BBB that is composed of endothelial cells (blue) surrounded by supportive pericytes (green) and astrocytic endfeet (pink). The basement membrane (light blue) is shared between pericytes and endothelial, while perivascular spaces (yellow) are located between the basement membrane and astrocytic endfeet and are filled with CSF. AQP4 channels on astrocytic endfeet mediate water flux into PVS. (B) In the glymphatic system, fluid movement is facilitated by AQP4 channels located on astrocytic endfeet, driving convective flow from the CSF-filled periarterial spaces to the perivenous spaces. This convective flow within the brain parenchyma is believed to contribute to the clearance of waste products from the brain. Subsequently, the parenchymal waste present in the CSF is drained into the peripheral lymphatics through the perivenous spaces.
Jnt 04 00020 g001
Table 1. Monoclonal Antibodies for CNS Diseases.
Table 1. Monoclonal Antibodies for CNS Diseases.
Alzheimer’s Disease
Name (Brand)TargetmAb TypeUS Approval (Status)
Aducanumab (Aduhelm)Amyloid betaHuman IgG12021
Lecanemab (Leqembi)Amyloid betaHumanized IgG12023
DonanemabAmyloid betaHumanized IgG12nd Review
LY3372993; RemternetugAmyloid betaHuman IgG1Phase 3
CrenezumabAmyloid betaHumanized IgG4Phase 3
GantenerumabAmyloid betaHuman IgG1Phase 3
SolanezumabMonomersHumanized IgG1Phase 3
E2814Tau proteinHumanized IgG1Phase 2/3
SemorinemabTau proteinHumanized IgG4Phase 2
BIB092Tau proteinHuman mAbPhase 2
ABBV-8E12Tau proteinHuman mAbPhase 2
ZagotenemabTau proteinHuman mAbPhase 2
JNJ-63733657Tau proteinHuman mAbPhase 1
AL002TREM-2 ReceptorHuman mAbPhase 1
AL003SIGLEC-3Human mAbPhase 1
Frontotemporal Dementia
AL001; LatozinemabSortilinHuman IgG1Phase 3
Glioblastoma
125I-mAb 425EGFRHuman mAbPhase 2
Depatuxizumab mafodotinEGFRIgG1 ADCPhase 2b/3
[188Re]-labeled NimotuzumabEGFRHumanized mAbPhase 1
131I-chTNT-1/B MAbDNA-histone H1 complexHuman mAbPhase 1/2
131I-BC-2 mAbTenascinHuman mAbPhase 2
211At-labeled 81C6 mAbTenascinHuman mAbPhase 1/2
biotin-coupled BC-4 +
Avidin + [90Y]-Biotin		TenascinHuman mAbPhase 1/2
Neuroblastoma
Dinutuximab (Unituxin)GD2Chimeric IgG12015
131I-omburtamabBT-H3Murine mAbPhase 2/3
Multiple Sclerosis (MS)
Daclizumab (Zinbryta)CD25Humanized IgG12016
Divozilimab (Ivlizi)CD20Humanized IgG12023
Ocrelizumab (OCREVU)CD20Humanized IgG12017
Ublituximab (BRIUMVI)CD20Humanized IgG12022
Alemtuzumab (Lemtrada)CD52Humanized IgG12014
Natalizumab (Tysabri)α4 integrinHumanized IgG42014
Adapted from Refs. [19,20,21].
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Schwinghamer, K.; Siahaan, T.J. Enhancing Antibody Exposure in the Central Nervous System: Mechanisms of Uptake, Clearance, and Strategies for Improved Brain Delivery. J. Nanotheranostics 2023, 4, 463-479. https://doi.org/10.3390/jnt4040020

AMA Style

Schwinghamer K, Siahaan TJ. Enhancing Antibody Exposure in the Central Nervous System: Mechanisms of Uptake, Clearance, and Strategies for Improved Brain Delivery. Journal of Nanotheranostics. 2023; 4(4):463-479. https://doi.org/10.3390/jnt4040020

Chicago/Turabian Style

Schwinghamer, Kelly, and Teruna J. Siahaan. 2023. "Enhancing Antibody Exposure in the Central Nervous System: Mechanisms of Uptake, Clearance, and Strategies for Improved Brain Delivery" Journal of Nanotheranostics 4, no. 4: 463-479. https://doi.org/10.3390/jnt4040020

APA Style

Schwinghamer, K., & Siahaan, T. J. (2023). Enhancing Antibody Exposure in the Central Nervous System: Mechanisms of Uptake, Clearance, and Strategies for Improved Brain Delivery. Journal of Nanotheranostics, 4(4), 463-479. https://doi.org/10.3390/jnt4040020

Article Metrics

Back to TopTop