Molecular Pharmaceutics · 14 authors, 1 centre
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Pabinafusp alfa, a transferrin receptor-targeted iduronate-2-sulfatase, crosses the blood-retinal barrier after intravenous administration in MPS II mice, reducing heparan sulfate accumulation in the retina and preserving retinal function. This treatment prevented photoreceptor loss and normalized electroretinography responses, whereas non-targeted enzyme replacement therapy did not. The findings suggest a potential therapeutic approach for retinopathy in MPS II patients.
**Background:** Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is a lysosomal storage disorder caused by deficiency of iduronate-2-sulfatase (IDS), leading to accumulation of glycosaminoglycans (GAGs) such as heparan sulfate (HS) and dermatan sulfate. Patients develop progressive retinopathy and vision loss, but conventional intravenous enzyme replacement therapy (ERT) with recombinant IDS cannot cross the blood-retinal barrier (BRB). Pabinafusp alfa is a fusion protein of IDS with an anti-human transferrin receptor (TfR) antibody designed to penetrate the blood-brain barrier via TfR-mediated transcytosis. Because the inner BRB expresses TfR similarly to the blood-brain barrier, the authors hypothesized that pabinafusp alfa could also reach the retina and treat retinopathy.
**Methods:** The study used MPS II model mice (Ids-KO and hTfR-KI/Ids-KO) on a C57BL/6 background. For retinal delivery assessment, mice received a single intravenous dose of pabinafusp alfa or nonfused IDS at 2 mg/kg; IDS distribution was detected by immunohistochemistry and quantified by electrochemiluminescence immunoassay 17 hours post-injection. For the long-term efficacy study, male hTfR-KI/Ids-KO mice (10 weeks old) were treated intravenously once weekly for 40 weeks with pabinafusp alfa (0.5 or 2 mg/kg), nonfused IDS (0.5 mg/kg), or saline. Wild-type hTfR-KI mice served as normal controls. Retinal function was assessed by scotopic electroretinography (ERG) at baseline and after 38 weeks of treatment, using single white-flash stimuli from 0.00001 to 10 cd s/cm². One week after the final dose, HS concentrations in retina, RPE/choroid/sclera complex, optic nerve, and visual cortex were measured. Histological analysis included H&E staining to measure outer nuclear layer (ONL) thickness and total retinal cell counts. Statistical comparisons used unpaired t-test (WT vs KO) and Tukey-Kramer test (between treatment groups), with significance set at P < 0.05.
**Key Results:** Immunostaining showed IDS enzyme in the retina only after pabinafusp alfa administration, not after nonfused IDS. Quantification confirmed measurable IDS exclusively in pabinafusp alfa-treated mice. In the long-term study, HS concentrations were markedly elevated in vehicle-treated MPS II mice in retina, RPE/choroid/sclera, optic nerve, and visual cortex. Nonfused IDS reduced HS only in the RPE/choroid/sclera complex (outside the BRB), whereas pabinafusp alfa reduced HS in all four tissues in a dose-related manner. ERG at baseline (10 weeks) showed decreased a-wave amplitude in MPS II mice (mean a-wave ~200 µV vs ~350 µV in WT, P < 0.001) but normal b-wave. After 38 weeks, vehicle-treated MPS II mice had profoundly reduced a-wave and b-wave amplitudes (a-wave ~50 µV, b-wave ~150 µV at 10 cd s/cm²) compared to WT (a-wave ~350 µV, b-wave ~500 µV). Nonfused IDS-treated mice showed no significant improvement. Pabinafusp alfa at 2 mg/kg restored a-wave and b-wave amplitudes to near WT levels (a-wave ~300 µV, b-wave ~450 µV), with statistical significance (P < 0.001 vs vehicle). Histological analysis revealed significant thinning of the ONL in vehicle-treated MPS II mice (mean ~40 µm vs ~55 µm in WT, P < 0.001). Pabinafusp alfa at 2 mg/kg preserved ONL thickness (~55 µm, P < 0.001 vs vehicle), while nonfused IDS showed only a slight, non-significant increase. Total retinal cell number was significantly reduced in vehicle-treated mice (~1.2 × 10⁶ cells vs ~2.0 × 10⁶ in WT, P < 0.001), and pabinafusp alfa at 2 mg/kg significantly prevented cell loss (~1.8 × 10⁶ cells, P < 0.01 vs vehicle).
**Clinical Implications:** This study demonstrates that TfR-targeted IDS (pabinafusp alfa) can cross the BRB and deliver therapeutic enzyme to the retina, reducing HS accumulation and preserving retinal structure and function in a mouse model of MPS II. The findings suggest that pabinafusp alfa, already approved in Japan for neuronopathic MPS II, may also address retinopathy—a common and debilitating complication not treatable with conventional ERT. The observed reversibility of early photoreceptor dysfunction in young mice highlights the potential benefit of early intervention. However, the study is limited by its animal model and lack of mechanistic detail on how HS deposition causes retinal damage. Further research is needed to confirm efficacy in human MPS II patients and to explore the specific cell types involved.