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

Abstract

Delivery of an interleukin-1 antagonist across the blood–brain barrier results in analgesia in the Seltzer model of neuropathic pain.

Enhanced Delivery of Galanin Conjugates to the Brain through Bioengineering of the Anti-Transferrin Receptor Antibody OX26

“…11,[14][15][16][17] Lowering their affinity facilitated their sorting into early endosomes, 18 improved their transcytosis and increased their levels in the brain parenchyma. 11,19 The comparisons of TfR engagement with bi>valent or monovalent TfR antibodies revealed that a monovalent format achieved improved transcytosis across the BBB, regardless of affinity, 12 whereas a high>affinity bi>valent antibody was destined to degradation in brain endothelial lysosomes. 12 A pH>sensitive bi>valent TfR antibody, with lower binding affinity at the acidic pH found in endocytic compartments, also demonstrated improved BBB transcytosis in vitro.…”

“…12 A pH>sensitive bi>valent TfR antibody, with lower binding affinity at the acidic pH found in endocytic compartments, also demonstrated improved BBB transcytosis in vitro. 13 Recent study also showed that the mouse anti>TfR antibody 8D3 bioengineered to reduce Kd 4 from 1.2 nM to 130 nM resulted in a 44>fold increase in total brain and spinal cord exposure 19 .…”

“…The same lower affinity variants improved the potency of the anti>nociceptive neuropeptide galanin when chemically linked to the antibodies in the Hargreaves pain model. The study demonstrates that the affinity optimization of anti>TfR antibodies improves their brain and CSF exposure in the absence of a monovalent binding to the receptor.Various bi>specific antibodies containing an antibody against a therapeutic target in the CNS, including Aβ 12,36 and BACE1,11,18 coupled to an anti>TfR antibody to enable transcytosis across the BBB have shown enhanced brain penetration in rodents11,12,19,36 and, in some cases, in non>human primates 37. Various formats of the anti>TfR antibody 'arm' have been fused with therapeutic antibodies, including a full IgG,36 a heterodimerized monovalent 'half' antibody, 11 mono> or bivalent fragment antigen binding -Fab,12 and shark single>domain antibody (VNAR) 38.…”

Blood-brain barrier transport using a high-affinity, brain-selective VNAR (Variable Domain of New Antigen Receptor) antibody targeting transferrin receptor 1

“…High affinity binding of antibodies to TfR1 appears to impede transcytosis by lysosomal targeting or preventing receptor dissociation consequently trapping the antibody inside the capillary endothelium [8,10,[36][37][38]. It was further shown that monovalent formatting or lowering the affinity of TfR1 antibodies could boost brain transport in vivo [8,[11][12][13]. Conversely, a series of biochemical, histological, biodistribution, pharmacokinetic and pharmacodynamic studies showed that neither high-affinity binding (0.6 nM KD) nor a bivalent configuration impeded BBB transport of TXB2-hFc via TfR1.…”

“…Anti-TfR1 antibodies can accumulate in brain capillaries with limited release into the brain parenchyma [8] and can direct the receptor for lysosomal degradation [9,10]. These antibodies have been subsequently re-engineered to reduce their safety liabilities and improve brain penetration either by monovalent formatting or a reduction in TfR1 binding affinity [8,[11][12][13].…”