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. 2017 Apr;158(4):660-668.
doi: 10.1097/j.pain.0000000000000810.

Enhanced delivery of IL-1 receptor antagonist to the central nervous system as a novel anti-transferrin receptor-IL-1RA fusion reverses neuropathic mechanical hypersensitivity

Affiliations

Enhanced delivery of IL-1 receptor antagonist to the central nervous system as a novel anti-transferrin receptor-IL-1RA fusion reverses neuropathic mechanical hypersensitivity

Carl I Webster et al. Pain. 2017 Apr.

Abstract

Neuropathic pain is a major unmet medical need, with only 30% to 35% of patients responding to the current standard of care. The discovery and development of novel therapeutics to address this unmet need have been hampered by poor target engagement, the selectivity of novel molecules, and limited access to the relevant compartments. Biological therapeutics, either monoclonal antibodies (mAbs) or peptides, offer a solution to the challenge of specificity as the intrinsic selectivity of these kinds of molecules is significantly higher than traditional medicinal chemistry-derived approaches. The interleukin-1 receptor system within the spinal cord has been implicated in the amplification of pain signals, and its central antagonism provides relief of neuropathic pain. Targeting the IL-1 system in the spinal cord with biological drugs, however, raises the even greater challenge of delivery to the central compartment. Targeting the transferrin receptor with monoclonal antibodies has proved successful in traversing the endothelial cell-derived blood-brain barrier and delivering proteins to the central nervous system. In this study, we describe a novel construct exemplifying an engineered solution to overcome these challenges. We have generated a novel anti-transferrin receptor-interleukin-1 receptor antagonist fusion that transports to the central nervous system and delivers efficacy in a model of nerve ligation-induced hypersensitivity. Approaches such as these provide promise for novel and selective analgesics that target the central compartment.

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Conflict of interest statement

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Figures

Figure 1.
Figure 1.
Effect of i.t. administered Kineret on the reversal of partial nerve ligation–induced mechanical hyperalgesia. Data are mean % ipsilateral/contralateral ratio ± SEM. N = 9 to 10 per group. +P < 0.05 Kineret (30 μg per mouse) vs PBS vehicle control; ***P < 0.001 Kineret (10 μg per mouse) vs PBS vehicle control. i.t., intrathecal; ns, not significant.
Figure 2.
Figure 2.
Plasma and brain exposure of anti-transferrin variants in a mouse PK assay. (A) Plasma PK of anti-TfR variants and isotype control (NIP228) over a 2-week period. N = 6 per group (B) Brain exposure as a measure of % injected dose per gram of brain. (C) Spinal cord exposure as a measure of % injected dose per gram of spinal cord. PK, pharmokinetic; TfR, transferrin receptor.
Figure 3.
Figure 3.
Plasma, brain, and spinal cord exposure of anti-transferrin variant-IL-1RA fusion in mouse PK assay. (A) Plasma PK of anti-TfR-IL-1RA variants and isotype control (NIP228) over a 2 week period. N = 6 per group (B) Brain exposure as a measure of % injected dose per gram of brain. (C) Spinal cord exposure as a measure of % injected dose per gram of spinal cord. PK, pharmokinetic; TfR, transferrin receptor.
Figure 4.
Figure 4.
Effect of IL-1RA-anti–TfR fusions on IL-1β–induced IL6 secretion from NIH-3T3 cells in culture. Data are expressed as % IL-1β–induced IL6 mean ± SEM. Cells were pretreated with IL-1RA-anti–TfR fusions for 30 minutes before IL-1β stimulation. TfR, transferrin receptor.
Figure 5.
Figure 5.
Effect of anti-transferrin-IL-1RA fusions on the reversal of partial nerve ligation induced mechanical hyperalgesia. N = 8 to 9 per group. **P < 0.01; ***P < 0.001 Op + NIP228 vs Op + 8D3610-IL-1RA; +++P < 0.001 Op + NIP228 vs Op + 8D3130-IL-1RA; ns, not significant (P > 0.5). s.c, subcutaneous.
Figure 6.
Figure 6.
Dose response of 8D3130-IL-1RA fusions on the reversal of partial nerve ligation–induced mechanical hyperalgesia. N = 8 to 9 per group. **P < 0.01; ***P < 0.001 Op + NIP228 vs Op + 8D3130-IL-1RA (100 mg/kg); +++P < 0.001 Op + NIP228 vs Op + 8D3130-IL-1RA (50 mg/kg); ###P < 0.001 Op + NIP228 vs Op + 8D3130-IL-1RA (20 mg/kg); ns not significant (P > 0.5). s.c, subcutaneous.

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