A Therapeutic Antibody Targeting BACE1 Inhibits Amyloid-β Production in Vivo

Atwal, Jasvinder K.; Chen, Yongmei; Chiu, Cecilia; Mortensen, Deborah L.; Meilandt, William J.; Liu, Yichin; Heise, Christopher E.; Hoyte, Kwame; Luk, Wilman; Lu, Yanmei; Peng, Kun; Wu, Ping; Rougé, Lionel; Zhang, Yingnan; Lazarus, Robert A.; Scearce‐Levie, Kimberly; Wang, Weiru; Wu, Yan; Tessier‐Lavigne, Marc; Watts, Ryan J.

doi:10.1126/scitranslmed.3002254

Cited by 258 publications

(204 citation statements)

References 33 publications

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“…1a). We have confirmed this proposed mechanism of antibody uptake in brain indirectly by showing that increasing the doses of anti-BACE1 antibodies (discussed later) results in increased CNS exposure in a nonsaturating fashion [29]. Furthermore, we have observed that brain uptake of IgG is comparable in both wild-type and severe combined immunodeficiency mice (unpublished data), suggesting that IgG does not compete for uptake at the BBB.…”

Section: Limited Quantities Of Therapeutic Antibodies Cross the Bbbsupporting

confidence: 68%

Developing Therapeutic Antibodies for Neurodegenerative Disease

Yu¹,

Watts²

2013

Neurotherapeutics

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180

171

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The central nervous system has been considered off-limits to antibody therapeutics. However, recent advances in preclinical and clinical drug development suggest that antibodies can cross the blood-brain barrier in limited quantities and act centrally to mediate their effects. In particular, immunotherapy for Alzheimer's disease has shown that targeting beta amyloid with antibodies can reduce pathology in both mouse models and the human brain, with strong evidence supporting a central mechanism of action. These findings have fueled substantial efforts to raise antibodies against other central nervous system targets, particularly neurodegenerative targets, such as tau, beta-secretase, and alpha-synuclein. Nevertheless, it is also apparent that antibody penetration across the blood-brain barrier is limited, with an estimated 0.1-0.2 % of circulating antibodies found in brain at steady-state concentrations. Thus, technologies designed to improve antibody uptake in brain are receiving increased attention and are likely going to represent the future of antibody therapy for neurologic diseases, if proven safe and effective. Herein we review briefly the progress and limitations of traditional antibody drug development for neurodegenerative diseases, with a focus on passive immunotherapy. We also take a more in-depth look at new technologies for improved delivery of antibodies to the brain.

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Section: Limited Quantities Of Therapeutic Antibodies Cross the Bbbsupporting

confidence: 68%

Developing Therapeutic Antibodies for Neurodegenerative Disease

Yu¹,

Watts²

2013

Neurotherapeutics

Self Cite

180

171

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“…Therefore, strategies are now available to overcome limits of BBB passage. Thus, antibodies engineered to be actively transported via BBB have been developed that were shown to be beneficial for the treatment of Alzheimer's disease (48,49). Cytokines including TNF can cross the BBB (50).…”

Section: Resultsmentioning

confidence: 99%

Essential protective role of tumor necrosis factor receptor 2 in neurodegeneration

Dong

Fischer

Naudé

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

137

158

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Despite the recognized role of tumor necrosis factor (TNF) in inflammation and neuronal degeneration, anti-TNF therapeutics failed to treat neurodegenerative diseases. Animal disease models had revealed the antithetic effects of the two TNF receptors (TNFR) in the central nervous system, whereby TNFR1 has been associated with inflammatory degeneration and TNFR2 with neuroprotection. We here show the therapeutic potential of selective inhibition of TNFR1 and activation of TNFR2 by ATROSAB, a TNFR1-selective antagonistic antibody, and EHD2-scTNF R2 , an agonistic TNFR2-selective TNF, respectively, in a mouse model of NMDA-induced acute neurodegeneration. Coadministration of either ATROSAB or EHD2-scTNF R2 into the magnocellular nucleus basalis significantly protected cholinergic neurons and their cortical projections against cell death, and reverted the neurodegeneration-associated memory impairment in a passive avoidance paradigm. Simultaneous blocking of TNFR1 and TNFR2 signaling, however, abrogated the therapeutic effect. Our results uncover an essential role of TNFR2 in neuroprotection. Accordingly, the therapeutic activity of ATROSAB is mediated by shifting the balance of the antithetic activity of endogenous TNF toward TNFR2, which appears essential for neuroprotection. Our data also explain earlier results showing that complete blocking of TNF activity by anti-TNF drugs was detrimental rather than protective and argue for the use of next-generation TNFR-selective TNF therapeutics as an effective approach in treating neurodegenerative diseases.

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“…delivered to the spinal cord can improve function after spinal cord injury (33,34), and new techniques may even allow antibodies into the brain for the treatment of neurodegenerative diseases (35,36). Additionally, the development of small-molecule antagonists of CS-E function should also be feasible by inhibiting the sulfotransferase Chst15.…”

Section: Discussionmentioning

confidence: 99%

A sulfated carbohydrate epitope inhibits axon regeneration after injury

Brown

Xia

Zhuang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

140

178

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Chondroitin sulfate proteoglycans (CSPGs) represent a major barrier to regenerating axons in the central nervous system (CNS), but the structural diversity of their polysaccharides has hampered efforts to dissect the structure-activity relationships underlying their physiological activity. By taking advantage of our ability to chemically synthesize specific oligosaccharides, we demonstrate that a sugar epitope on CSPGs, chondroitin sulfate-E (CS-E), potently inhibits axon growth. Removal of the CS-E motif significantly attenuates the inhibitory activity of CSPGs on axon growth. Furthermore, CS-E functions as a protein recognition element to engage receptors including the transmembrane protein tyrosine phosphatase PTPσ, thereby triggering downstream pathways that inhibit axon growth. Finally, masking the CS-E motif using a CS-Especific antibody reversed the inhibitory activity of CSPGs and stimulated axon regeneration in vivo. These results demonstrate that a specific sugar epitope within chondroitin sulfate polysaccharides can direct important physiological processes and provide new therapeutic strategies to regenerate axons after CNS injury.

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A Therapeutic Antibody Targeting BACE1 Inhibits Amyloid-β Production in Vivo

Cited by 258 publications

References 33 publications

Developing Therapeutic Antibodies for Neurodegenerative Disease

Developing Therapeutic Antibodies for Neurodegenerative Disease

Essential protective role of tumor necrosis factor receptor 2 in neurodegeneration

A sulfated carbohydrate epitope inhibits axon regeneration after injury

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