Effects of wearable ankle robotics for stair and over-ground training on sub-acute stroke: a randomized controlled trial.

BACKGROUND: Wearable ankle robotics could potentially facilitate intensive repetitive task-specific gait training on stair environment for stroke rehabilitation. A lightweight (0.5 kg) and portable exoskeleton ankle robot was designed to facilitate over-ground and stair training either providing active assistance to move paretic ankle augmenting residual motor function (power-assisted ankle robot, PAAR), or passively support dropped foot by lock/release ankle joint for foot clearance in swing phase (swing-controlled ankle robot, SCAR). In this two-center randomized controlled trial, we hypothesized that conventional training integrated with robot-assisted gait training using either PAAR or SCAR in stair environment are more effective to enhance gait recovery and promote independency in early stroke, than conventional training alone. METHODS: Sub-acute stroke survivors (within 2 months after stroke onset) received conventional training integrated with 20-session robot-assisted training (at least twice weekly, 30-min per session) on over-ground and stair environments, wearing PAAR (n = 14) or SCAR (n = 16), as compared to control group receiving conventional training only (CT, n = 17). Clinical assessments were performed before and after the 20-session intervention, including functional ambulatory category as primary outcome measure, along with Berg balance scale and timed 10-m walk test. RESULTS: After the 20-session interventions, all three groups showed statistically significant and clinically meaningful within-group functional improvement in all outcome measures (p < 0.005). Between-group comparison showed SCAR had greater improvement in functional ambulatory category (mean difference + 0.6, medium effect size 0.610) with more than 56% independent walkers after training, as compared to only 29% for CT. Analysis of covariance results showed PAAR had greater improvement in walking speed than SCAR (mean difference + 0.15 m/s, large effect size 0.752), which was in line with the higher cadence and speed when wearing the robot during the 20-session robot-assisted training over-ground and on stairs. CONCLUSIONS: Robot-assisted stair training would lead to greater functional improvement in gait independency and walking speed than conventional training in usual care. The active powered ankle assistance might facilitate users to walk more and faster with their paretic leg during stair and over-ground walking. TRIAL REGISTRATION: ClinicalTrials.gov NCT03184259. Registered on 12 June 2017.

Effector-attenuating Substitutions That Maintain Antibody Stability and Reduce Toxicity in Mice.

The antibody Fc region regulates antibody cytotoxic activities and serum half-life. In a therapeutic context, however, the cytotoxic effector function of an antibody is often not desirable and can create safety liabilities by activating native host immune defenses against cells expressing the receptor antigens. Several amino acid changes in the Fc region have been reported to silence or reduce the effector function of antibodies. These earlier studies focused primarily on the interaction of human antibodies with human Fc-γ receptors, and it remains largely unknown how such changes to Fc might translate to the context of a murine antibody. We demonstrate that the commonly used N297G (NG) and D265A, N297G (DANG) variants that are efficacious in attenuating effector function in primates retain potent complement activation capacity in mice, leading to safety liabilities in murine studies. In contrast, we found an L234A, L235A, P329G (LALA-PG) variant that eliminates complement binding and fixation as well as Fc-γ-dependent, antibody-dependent, cell-mediated cytotoxity in both murine IgG2a and human IgG1. These LALA-PG substitutions allow a more accurate translation of results generated with an "effectorless" antibody between mice and primates. Further, we show that both human and murine antibodies containing the LALA-PG variant have typical pharmacokinetics in rodents and retain thermostability, enabling efficient knobs-into-holes bispecific antibody production and a robust path to generating highly effector-attenuated bispecific antibodies for preclinical studies.

Blocking neuropilin-1 function has an additive effect with anti-VEGF to inhibit tumor growth.

Neuropilin-1 (NRP1) guides the development of the nervous and vascular systems. Binding to either semaphorins or VEGF, NRP1 acts with plexins to regulate neuronal guidance, or with VEGFR2 to mediate vascular development. We have generated two monoclonal antibodies that bind to the Sema- and VEGF-binding domains of NRP1, respectively. Both antibodies reduce angiogenesis and vascular remodeling, while having little effect on other VEGFR2-mediated events. Importantly, anti-NRP1 antibodies have an additive effect with anti-VEGF therapy in reducing tumor growth. Vessels from tumors treated with anti-VEGF show a close association with pericytes, while tumors treated with both anti-NRP1 and anti-VEGF lack this organization. We propose that blocking NRP1 function inhibits vascular remodeling, rendering vessels more susceptible to anti-VEGF therapy.

CD98hc is a target for brain delivery of biotherapeutics.

Brain exposure of systemically administered biotherapeutics is highly restricted by the blood-brain barrier (BBB). Here, we report the engineering and characterization of a BBB transport vehicle targeting the CD98 heavy chain (CD98hc or SLC3A2) of heterodimeric amino acid transporters (TVCD98hc). The pharmacokinetic and biodistribution properties of a CD98hc antibody transport vehicle (ATVCD98hc) are assessed in humanized CD98hc knock-in mice and cynomolgus monkeys. Compared to most existing BBB platforms targeting the transferrin receptor, peripherally administered ATVCD98hc demonstrates differentiated brain delivery with markedly slower and more prolonged kinetic properties. Specific biodistribution profiles within the brain parenchyma can be modulated by introducing Fc mutations on ATVCD98hc that impact FcγR engagement, changing the valency of CD98hc binding, and by altering the extent of target engagement with Fabs. Our study establishes TVCD98hc as a modular brain delivery platform with favorable kinetic, biodistribution, and safety properties distinct from previously reported BBB platforms.

Immediate Effects of Functional Electrical Stimulation-Assisted Cycling on the Paretic Muscles of Patients With Hemiparesis After Stroke: Evidence From Electrical Impedance Myography.

Background: Electrical impedance myography (EIM) has been applied to assess muscle health conditions in neuromuscular disorders. This study aimed to detect immediate muscle electrical impedance property alterations in lower extremity of chronic stroke survivors immediately after functional electrical stimulation (FES)-assisted cycling training. Methods: Fourteen chronic stroke survivors were recruited for the current study. EIM measurements were conducted before and immediately after 40-min FES-assisted cycling training for each subject. Four interested muscle groups [rectus femoris (RF), biceps femoris (BF), tibialis anterior (TA), and the medial head of gastrocnemius (MG)] were selected. Correlation analysis was performed to reveal a significant correlation between changes in EIM parameters and clinical scales [Fugl-Meyer Assessment of the lower extremity (FMA-LE); 6-min walking test (6MWT)]. Results: Immediately after training, reactance (X) and phase angle (θ) values significantly increased on the TA and MG muscles. Significant correlation was observed between X value and FMA-LE scores (r = 0.649, p = 0.012) at MG as well as X and FMA scores of the ankle joint (r = 0.612, p = 0.02). Resistance (R) and θ were significantly correlated with 6MWT score (R-6MWT: r = 0.651, p = 0.012; θ-6MWT: r = 0.621, p = 0.018). Conclusion: This brief report demonstrated that EIM can reveal the intrinsic property alteration in the paretic muscle of chronic stroke survivors immediately after FES-assisted cycling training. These alterations might be related to muscle hypertrophy (i.e., increases in muscle fiber size). This brief report might aid the understanding of the mechanism of electrical stimulation-assisted exercise in improving muscle function of stroke survivors.

MR angiogenesis imaging with Robo4- vs. alphaVbeta3-targeted nanoparticles in a B16/F10 mouse melanoma model.

The primary objective of this study was to utilize MR molecular imaging to compare the 3-dimensional spatial distribution of Robo4 and α(V)ß(3)-integrin as biosignatures of angiogenesis, in a rapidly growing, syngeneic tumor. B16-F10 melanoma-bearing mice were imaged with magnetic resonance (MR; 3.0 T) 11 d postimplantation before and after intravenous administration of either Robo4- or α(V)ß(3)-targeted paramagnetic nanoparticles. The percentage of MR signal-enhanced voxels throughout the tumor volume was low and increased in animals receiving α(V)ß(3)- and Robo4-targeted nanoparticles. Neovascular signal enhancement was predominantly associated with the tumor periphery (i.e., outer 50% of volume). Microscopic examination of tumors coexposed to the Robo4- and α(V)ß(3)-targeted nanoparticles corroborated the MR angiogenesis mapping results and further revealed that Robo4 expression generally colocalized with α(V)ß(3)-integrin. Robo4- and α(V)ß(3)-targeted nanoparticles were compared to irrelevant or nontargeted control groups in all modalities. These results suggest that α(V)ß(3)-integrin and Robo4 are useful biomarkers for noninvasive MR molecular imaging in syngeneic mouse tumors, but α(V)ß(3)-integrin expression was more detectable by MR at 3.0 T than Robo4. Noninvasive, neovascular assessments of the MR signal of Robo4, particularly combined with α(V)ß(3)-integrin expression, may help define tumor character prior to and following cancer therapy.

Functional brain networks assessed with surface electroencephalography for predicting motor recovery in a neural guided intervention for chronic stroke.

Predicting whether a chronic stroke patient is likely to benefit from a specific intervention can help patients establish reasonable expectations. It also provides the basis for candidates selecting for the intervention. Recent convergent evidence supports the value of network-based approach for understanding the relationship between dysfunctional neural activity and motor deficits after stroke. In this study, we applied resting-state brain connectivity networks to investigate intervention-specific predictive biomarkers of motor improvement in 22 chronic stroke participants who received either combined action observation with EEG-guided robot-hand training (Neural Guided-Action Observation Group, n = 12, age: 34-68 years) or robot-hand training without action observation and EEG guidance (non-Neural Guided-text group, n = 10, age: 42-57 years). The robot hand in Neural Guided-Action Observation training was activated only when significant mu suppression (8-12 Hz) was detected from participant's EEG signals in ipsilesional hemisphere while it was randomly activated in non-Neural Guided-text training. Only the Neural Guided-Action Observation group showed a significant long-term improvement in their upper-limb motor functions (P < 0.5). In contrast, no significant training effect on the paretic motor functions was found in the non-Neural Guided-text group (P > 0.5). The results of brain connectivity estimated via EEG coherence showed that the pre-training interhemispheric connectivity of delta, theta, alpha and contralesional connectivity of beta were motor improvement related in the Neural Guided-Action Observation group. They can not only differentiate participants with good and poor recovery (interhemispheric delta: P = 0.047, Hedges' g = 1.409; interhemispheric theta: P = 0.046, Hedges' g = 1.333; interhemispheric alpha: P = 0.038, Hedges' g = 1.536; contralesional beta: P = 0.027, Hedges' g = 1.613) but also significantly correlated with post-training intervention gains (interhemispheric delta: r = -0.901, P < 0.05; interhemispheric theta: r = -0.702, P < 0.05; interhemispheric alpha: r = -0.641, P < 0.05; contralesional beta: r = -0.729, P < 0.05). In contrast, no EEG coherence was significantly correlated with intervention gains in the non-Neural Guided-text group (all P s > 0.05 ). Partial least square regression showed that the combination of pre-training interhemispheric and contralesional local connectivity could precisely predict intervention gains in the Neural Guided-Action Observation group with a strong correlation between predicted and observed intervention gains (r = 0.82 r = 0.82 ) and between predicted and observed intervention outcomes (r = 0.90 r = 0.90 ). In summary, EEG-based resting-state brain connectivity networks may serve clinical decision-making by offering an approach to predicting Neural Guided-Action Observation training-induced motor improvement.

Muscle endurance time estimation during isometric training using electromyogram and supervised learning.

Constant-force isometric muscle training is useful for increasing the maximal strength , rehabilitation and work-fatigue assessment. Earlier studies have shown that muscle fatigue characteristics can be used for evaluating muscle endurance limit. STUDY OBJECTIVE: To predict muscle endurance time during isometric task using frequency spectrum characteristics of surface electromyography signals along with analysis of frequency spectrum shape and scale during fatigue accumulation. METHOD: Thirteen subjects performed isometric lateral raise at 60% MVC of deltoid (lateral) till endurance limit. Time windowed sEMG frequency spectrum was modelled using 2-parameter distributions namely Gamma and Weibull for spectrum analysis and endurance prediction. RESULTS: Gamma distribution provided better spectrum fitting (P < 0.001) than Weibull distribution. Spectrum Distribution demonstrated no change in shape but shifted towards lower frequency with increase of magnitude at characteristic mode frequency. Support Vector Regression based algorithm was developed for endurance time estimation using features derived from fitted frequency spectrum. Time taken till endurance limit for acquired dataset 38.53 ± 17.33 s (Mean ± Standard Deviation) was predicted with error of 0.029 ± 4.19 s . R-square: 0.956, training and test sets RMSE was calculated as 3.96 and 4.29 s respectively. The application of the algorithm suggested that model required 70% of sEMG signal from maximum time of endurance for high prediction accuracy. CONCLUSION: Endurance Limit prediction algorithm was developed for quantification of endurance time for optimizing isometric training and rehabilitation. Our method could help personalize and change conventional training method of same weight and duration for all subjects with optimized training parameters, based upon individual sEMG activity.

Modulation of Functional Connectivity and Low-Frequency Fluctuations After Brain-Computer Interface-Guided Robot Hand Training in Chronic Stroke: A 6-Month Follow-Up Study.

Hand function improvement in stroke survivors in the chronic stage usually plateaus by 6 months. Brain-computer interface (BCI)-guided robot-assisted training has been shown to be effective for facilitating upper-limb motor function recovery in chronic stroke. However, the underlying neuroplasticity change is not well understood. This study aimed to investigate the whole-brain neuroplasticity changes after 20-session BCI-guided robot hand training, and whether the changes could be maintained at the 6-month follow-up. Therefore, the clinical improvement and the neurological changes before, immediately after, and 6 months after training were explored in 14 chronic stroke subjects. The upper-limb motor function was assessed by Action Research Arm Test (ARAT) and Fugl-Meyer Assessment for Upper-Limb (FMA), and the neurological changes were assessed using resting-state functional magnetic resonance imaging. Repeated-measure ANOVAs indicated that long-term motor improvement was found by both FMA (F[2,26] = 6.367, p = 0.006) and ARAT (F[2,26] = 7.230, p = 0.003). Seed-based functional connectivity analysis exhibited that significantly modulated FC was observed between ipsilesional motor regions (primary motor cortex and supplementary motor area) and contralesional areas (supplementary motor area, premotor cortex, and superior parietal lobule), and the effects were sustained after 6 months. The fALFF analysis showed that local neuronal activities significantly increased in central, frontal and parietal regions, and the effects were also sustained after 6 months. Consistent results in FC and fALFF analyses demonstrated the increase of neural activities in sensorimotor and fronto-parietal regions, which were highly involved in the BCI-guided training. Clinical Trial Registration: This study has been registered at ClinicalTrials.gov with clinical trial registration number NCT02323061.

Robotic Glove with Soft-Elastic Composite Actuators for Assisting Activities of Daily Living.

Soft robotic hand/gloves for hand rehabilitation can aid the performance of activities of daily living (ADL). Although existing soft robotic hands can assist with finger flexion, few have addressed finger extension, which is a challenging task for stroke patients due to poststroke spasticity. In this article, we describe the design of a composite actuator, the soft-elastic composite actuator (SECA), to facilitate both finger flexion and extension. A double-segmented SECA comprising two serially connected fiber-reinforced actuators with two bottom torque-compensating layers was fabricated. The SECA bends and extends by pneumatic actuation, and the torque-compensating layers offer an assistive bending moment to configure the bending moment inside the SECA. The principles associated with selection of the torque-compensating layer are described. Analytical models were established to quantify the input pressure and the bending angle of SECA with free bending and when placed on a model compromised hand. The analytical models were validated experimentally and by the finite element method. Moreover, a stroke survivor was recruited to test the new robotic glove integrated with the multiple double-segmented SECA. The robotic glove facilitated hand opening and closing by the patient, and successfully assisted with grasp of a Chinese chess piece and twisting of a towel.

Design of a 3D Printed Soft Robotic Hand for Stroke Rehabilitation and Daily Activities Assistance.

In this paper, we present the new personalized 3D printed soft robotic hand for providing rehabilitation training and daily activities assistance to stroke survivors. The Soft-Elastic Composite Actuator (SECA) on the robotic hand is direct 3D printed to accommodate with different finger sizes. Flexion and extension can be actively facilitated on the SECA using the same pressurizing source. Iterative learning model predictive control (ILMPC) method is used to be the control algorithm of SECA. At 160 kPa of maximum input pressure, results show that the actuator bending angles can reach to 137 °, and tip output force can also reach to 2.45 N. Multiple 3D printed SECAs are integrated to a 3D printed hand base and then to be worn on stroke survivors. Two stroke survivors are recruited to evaluate the intention-based rehabilitation training with the 3D printed soft robotic hand, which improvement of their hand function can be observed on performing some daily tasks such as grasping a coin.

A pilot study of randomized clinical controlled trial of gait training in subacute stroke patients with partial body-weight support electromechanical gait trainer and functional electrical stimulation: six-month follow-up.

BACKGROUND AND PURPOSE: This study aimed to assess the effectiveness of gait training using an electromechanical gait trainer with or without functional electrical stimulation for people with subacute stroke. METHODS: This was a nonblinded randomized controlled trial with a 6-month follow-up. Fifty-four subjects were recruited within 6 weeks after stroke onset and were randomly assigned to 1 of 3 gait intervention groups: conventional overground gait training treatment (CT, n=21), electromechanical gait trainer (GT, n=17) and, electromechanical gait trainer with functional electrical stimulation (GT-FES, n=16). All subjects were to undergo an assigned intervention program comprising a 20-minute session every weekday for 4 weeks. The outcome measures were Functional Independence Measure, Barthel Index, Motricity Index leg subscale, Elderly Mobility Scale (EMS), Berg Balance Scale, Functional Ambulatory Category (FAC), and 5-meter walking speed test. Assessments were made at baseline, at the end of the 4-week intervention program, and 6 months after the program ended. RESULTS: By intention-to-treat and multivariate analysis, statistically significant differences showed up in EMS (Wilks' lambda=0.743, P=0.005), FAC (Wilks' lambda=0.744, P=0.005) and gait speed (Wilks' lambda=0.658, P<0.0001). Post hoc analysis (univariate 2-way ANCOVA) revealed that the GT and GT-FES groups showed significantly better improvement in comparison with the CT group at the end of the 4 weeks of training and in the 6-month follow-up. CONCLUSIONS: For the early stage after stroke, this study indicated a higher effectiveness in poststroke gait training that used an electromechanical gait trainer compared with conventional overground gait training. The training effect was sustained through to the 6-month follow-up after the intervention.

Development and Evaluation of a Kinect-based Rapid Movement Therapy Training Platform for Balance Rehabilitation.

With the growing aging and overall population, the demand for healthcare professionals and their burden increases by time. Effective balance recovery reaction is required to prevent falls. The aim of this project is to provide low-cost portable balance training system that trains the two important components of effective balance recovery reaction: faster movement completion time (MT) and larger range of motion (ROM). This is done by a Kinect-based interactive rapid movement therapy training platform for reaching and stepping actions. The platform provides real-time feedback to the patient, generates a report for healthcare professionals to monitor the patient's progress, and can be utilized in patient's home or community centers. A pilot study to test the platform was conducted on seventeen stroke patients and it has shown significant improvement in both MT (faster) and ROM (larger).

How to prepare a person with complete spinal cord injury to use surface electrodes for FES trike cycling.

Functional Electrical Stimulation (FES) cycling could benefit people with Spinal Cord Injury (SCI). The FES cycling involves large muscle groups during the training, and thus improves the cardiovascular function, increases the muscle bulk and reduces the secondary complications. This study developed an outdoor FES exercise cycling system for complete SCI persons to exercise their lower limbs without putting extra load on upper extremities. The mechanical structure of the cycling system was specially redesigned to secure the SCI persons in the cycling system. A six-phase-angle-driven control algorithm was designed to stimulate the quadriceps and hamstrings muscles. Two training modes, i.e., continuous mode and on-off mode, were designed and tested to increase the duration of the electrical stimulation to reduce muscle fatigue. A complete SCI volunteer participated in this training for six months. Beneficial effects could be observed such as paralyzed lower limb muscles had regained the muscle mass and reduced edema from the improved blood circulation. Moreover, the SCI volunteer attended the Cybathlon FES-bike competition in Zurich in October 2016 with Team Phoenix from the CUHK.

Tethered-variable CL bispecific IgG: an antibody platform for rapid bispecific antibody screening.

Bispecific antibodies offer a clinically validated platform for drug discovery. In generating functionally active bispecific antibodies, it is necessary to identify a unique parental antibody pair to merge into a single molecule. However, technologies that allow high-throughput production of bispecific immunoglobulin Gs (BsIgGs) for screening purposes are limited. Here, we describe a novel bispecific antibody format termed tethered-variable CLBsIgG (tcBsIgG) that allows robust production of intact BsIgG in a single cell line, concurrently ensuring cognate light chain pairing and preserving key antibody structural and functional properties. This technology is broadly applicable in the generation of BsIgG from a variety of antibody isotypes, including human BsIgG1, BsIgG2 and BsIgG4. The practicality of the tcBsIgG platform is demonstrated by screening BsIgGs generated from FGF21-mimetic anti-Klotho-ß agonistic antibodies in a combinatorial manner. This screen identified multiple biepitopic combinations with enhanced agonistic activity relative to the parental monoclonal antibodies, thereby demonstrating that biepitopic antibodies can acquire enhanced functionality compared to monospecific parental antibodies. By design, the tcBsIgG format is amenable to high-throughput production of large panels of bispecific antibodies and thus can facilitate the identification of rare BsIgG combinations to enable the discovery of molecules with improved biological function.

Gait training of patients after stroke using an electromechanical gait trainer combined with simultaneous functional electrical stimulation.

BACKGROUND AND PURPOSE: This case report describes the implementation of gait training intervention that used an electromechanical gait trainer with simultaneous functional electrical stimulation (FES) for 2 patients with acute ischemic stroke. CASE DESCRIPTION: Two individuals with post-stroke hemiplegia of less than 6 weeks' duration participated in a 4-week gait training program as an adjunct to physical therapy received at a hospital. After the 4-week intervention, both patients were discharged from the hospital, and they returned after 6 months for a follow-up evaluation. OUTCOMES: By the end of the 4-week intervention, both patients had shown improvements in scores on the Barthel Index, Berg Balance Scale, Functional Ambulation Categories Scale, 5-m timed walking test, and Motricity Index. In the 6-month follow-up evaluation, both patients continued to have improvements in all outcome measures. DISCUSSION: This case report shows that, following the use of an electromechanical gait trainer simultaneously with FES, patients after acute stroke had improvements in gait performance, functional activities, balance, and motor control in the long term.

Discovery of Novel Blood-Brain Barrier Targets to Enhance Brain Uptake of Therapeutic Antibodies.

The blood-brain barrier (BBB) poses a major challenge for developing effective antibody therapies for neurological diseases. Using transcriptomic and proteomic profiling, we searched for proteins in mouse brain endothelial cells (BECs) that could potentially be exploited to transport antibodies across the BBB. Due to their limited protein abundance, neither antibodies against literature-identified targets nor BBB-enriched proteins identified by microarray facilitated significant antibody brain uptake. Using proteomic analysis of isolated mouse BECs, we identified multiple highly expressed proteins, including basigin, Glut1, and CD98hc. Antibodies to each of these targets were significantly enriched in the brain after administration in vivo. In particular, antibodies against CD98hc showed robust accumulation in brain after systemic dosing, and a significant pharmacodynamic response as measured by brain Aß reduction. The discovery of CD98hc as a robust receptor-mediated transcytosis pathway for antibody delivery to the brain expands the current approaches available for enhancing brain uptake of therapeutic antibodies.

Operational redundancy in axon guidance through the multifunctional receptor Robo3 and its ligand NELL2.

Axon pathfinding is orchestrated by numerous guidance cues, including Slits and their Robo receptors, but it remains unclear how information from multiple cues is integrated or filtered. Robo3, a Robo family member, allows commissural axons to reach and cross the spinal cord midline by antagonizing Robo1/2-mediated repulsion from midline-expressed Slits and potentiating deleted in colorectal cancer (DCC)-mediated midline attraction to Netrin-1, but without binding either Slits or Netrins. We identified a secreted Robo3 ligand, neural epidermal growth factor-like-like 2 (NELL2), which repels mouse commissural axons through Robo3 and helps steer them to the midline. These findings identify NELL2 as an axon guidance cue and establish Robo3 as a multifunctional regulator of pathfinding that simultaneously mediates NELL2 repulsion, inhibits Slit repulsion, and facilitates Netrin attraction to achieve a common guidance purpose.

Therapeutic bispecific antibodies cross the blood-brain barrier in nonhuman primates.

Using therapeutic antibodies that need to cross the blood-brain barrier (BBB) to treat neurological disease is a difficult challenge. We have shown that bispecific antibodies with optimized binding to the transferrin receptor (TfR) that target ß-secretase (BACE1) can cross the BBB and reduce brain amyloid-ß (Aß) in mice. Can TfR enhance antibody uptake in the primate brain? We describe two humanized TfR/BACE1 bispecific antibody variants. Using a human TfR knock-in mouse, we observed that anti-TfR/BACE1 antibodies could cross the BBB and reduce brain Aß in a TfR affinity-dependent fashion. Intravenous dosing of monkeys with anti-TfR/BACE1 antibodies also reduced Aß both in cerebral spinal fluid and in brain tissue, and the degree of reduction correlated with the brain concentration of anti-TfR/BACE1 antibody. These results demonstrate that the TfR bispecific antibody platform can robustly and safely deliver therapeutic antibody across the BBB in the primate brain.