Taken together, these results show that pabinafusp alfa brought about the improvement or stabilization of neurocognitive impairment in 89% of patients with MPS-II irrespective of their subtypes at week 52, and in 75% of them at week 104. Table 1 Changes in AE scores on KSPD (for Japan), BSID-III, and KABCII (for Brazil). efficacy and provided an acceptable safety profile. To date, pabinafusp alfa is the only approved intravenous ERT that is effective against both the somatic and CNS symptoms of patients with MPS-II. This article summarizes the previously obtained preclinical and clinical evidence related to the use of this drug, presents latest data, and discusses the preclinical, translational, and clinical challenges of evaluating, ameliorating, and preventing neurodegeneration in patients with MPS-II. = 3C5). 2.1.3. Prevention of Neuroinflammation and Subsequent NeurodegenerationThe neurodegenerative processes in MPS II mice were preceded by the activation of glial cells [21,22]. For instance, the intensity of glial fibrillary acidic protein (GFAP) signals increased in the astroglia, as did the number of CD68-positive microglia in the brain cortex (Figure 3). These histopathological changes were suppressed by chronic intravenous treatment with pabinafusp alfa (Figure 3). The relief from neuroinflammation afforded by pabinafusp alfa further prevented (-)-(S)-B-973B morphological abnormalities and neuronal death in the brains of untreated MPS II mice (Figure 3), whereas idursulfase was found to be ineffective against these pathological changes in the brain . (-)-(S)-B-973B Open in a separate window Figure 3 Prevention of neuroinflammation and neurodegeneration by pabinafusp alfa in MPS (-)-(S)-B-973B II mouse brains. Specimens from the brain cortex were stained with GFAP (top), CD68 (middle), and hematoxylin/eosin (bottom). Data are from a 36-week study. Arrows indicate the vacuolation of neuronal cells. Scale bars, 50m. Updated from . 2.1.4. Prevention of Neurocognitive AbnormalitiesIn MPS II mice, progressive neurocognitive impairments manifest themselves as a loss of spatial learning ability, which can be assessed using the Morris water maze test . When normal healthy mice were subjected to the test, the time taken to reach the platform (goal latency) became shorter day by day, whereas untreated (-)-(S)-B-973B MPS II mice experienced difficulty in learning how to reach the platform  (Figure 4). The mice receiving chronic treatment with pabinafusp alfa maintained their spatial learning ability, unlike the wild-type animals (Figure 4). Idursulfase failed to prevent the loss of learning ability, so the attenuation of neurocognitive abnormalities observed in the pabinafusp alfa-treated MPS II mice can be primarily attributed to the clearance of HS deposited in the brain. In other words, a high HS concentration ICAM2 in the brain can be viewed as a good predictor of neurodegeneration as well as a marker of drug efficacy in patients with neuronopathic MPS II. Open in a separate window Figure 4 Maintenance of spatial learning abilities in MPS II mice receiving chronic treatment with pabinafusp alfa. After 36 weeks of treatment, spatial learning ability was assessed with the Morris water maze test. The time to reach the platform (goal latency) was measured 3 times per day and the means were calculated within each day for individual animals. Values are presented as the mean with S.E. for each group (= 12C15). Paired 0.01 (Day 1 vs. Day 5). EW, every week; EoW, every other week. Reproduced from . 2.1.5. Identification of biomarker for CNS efficacyThanks to the weakness of the barrier between the brain parenchyma and the cerebrospinal fluid (CSF) , HS concentrations in the brain are considered to be directly correlated with those in the CSF, as demonstrated by the high correlations we found between the intracerebral and CSF HS concentrations in the MPS II mice treated with pabinafusp alfa (Figure 5). Thus, HS concentrations in the CSF are a useful and practical surrogate biomarker for monitoring drug efficacy in patients with neuronopathic MPS II, because HS concentrations in the brain cannot (-)-(S)-B-973B be measured in clinical settings. Open in a separate window Figure 5 Correlation between concentrations of HS in the brains and the CSF of MPS II mice treated with pabinafusp alfa. Results from studies of single-dose, 4-week, 8-week, 12-week, and 36-week treatments are included. 2.2. Preclinical Safety Results In vitro assay systems were used to comprehensively evaluate the preclinical safety of pabinafusp alfa in cynomolgus monkeys. Since pabinafusp alfa contains an entire IgG structure in its molecule, its safety evaluation needs to involve antibody-associated functions, such as effector functions relevant to cytotoxicity . In this regard, the potential effects of pabinafusp alfa on antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) were examined with TfR-expressing hematopoietic cells, which elicited neither ADCC nor CDC . Consistent.