Brain Access of Monoclonal Antibodies as Imaged and Quantified by <sup>89</sup>Zr-Antibody PET: Perspectives for Treatment of Brain Diseases

Zanten, Sophie E M Veldhuijzen van; Hamer, Philip C. De Witt; Dongen, Guus A.M.S. van

doi:10.2967/jnumed.118.220939

Cited by 14 publications

(13 citation statements)

References 12 publications

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“…This problem is especially evident for biologicals such as monoclonal antibodies (mAbs) that are relatively large molecules. To overcome the presumed drug delivery obstacle in the brain, many treatment strategies for CNS diseases are directed at disrupting, passing, or bypassing the effective BBB [45,46]. Disruption has been tried chemically, by drugs that influence passive diffusion (e.g., bradykinin, mannitol, regadenoson, and borneol) or active transport mechanisms (e.g., elacridar), or by radiotherapy, ultrasound, or microwaves.…”

Section: Discussionmentioning

confidence: 99%

IC100: a novel anti-ASC monoclonal antibody improves functional outcomes in an animal model of multiple sclerosis

Desu

Plastini

Illiano

et al. 2020

J Neuroinflammation

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Background: The inflammasome adaptor apoptosis-associated speck-like protein containing a CARD (ASC) is involved in immune signaling by bridging the interactions between inflammasome sensors and caspase-1. Strong experimental evidence has shown that ASC −/− mice are protected from disease progression in animal models of multiple sclerosis (MS), suggesting that targeting inflammasome activation via ASC inhibition may be a promising therapeutic strategy in MS. Thus, the goal of our study is to test the efficacy of IC100, a novel humanized antibody targeting ASC, in preventing and/or suppressing disease in the experimental autoimmune encephalomyelitis (EAE) model of MS. Methods: We employed the EAE model of MS where disease was induced by immunization of C57BL/6 mice with myelin oligodendrocyte glycoprotein peptide 35-55 (MOG 35-55). Mice were treated with vehicle or increasing doses of IC100 (10, 30, and 45 mg/kg) and clinical disease course was evaluated up to 35 days post EAE induction. Immune cell infiltration into the spinal cord and microglia responses were assessed. Results: We show that IC100 treatment reduced the severity of EAE when compared to vehicle-treated controls. At a dose of 30 mg/kg, IC100 significantly reduced the number of CD4 + and CD8 + T cells and CD11b + MHCII + activated myeloid cells entering the spinal cord from the periphery, and reduced the number of total and activated microglia. Conclusions: These data indicate that IC100 suppresses the immune-inflammatory response that drives EAE development and progression, thereby identifying ASC as a promising target for the treatment of MS as well as other neurological diseases with a neuroinflammatory component.

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Section: Discussionmentioning

confidence: 99%

IC100: a novel anti-ASC monoclonal antibody improves functional outcomes in an animal model of multiple sclerosis

Desu

Plastini

Illiano

et al. 2020

J Neuroinflammation

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“…Recently, radiolabeled antibodies have been imaged to quantify the penetration through the blood-brain barrier. It is also known that antibody penetration across the BBB is more into the brain areas which are severely affected by tumors [63]. However, as mentioned above, strokes may lead to the massive disruption of the BBB and interestingly, ischemic brain regions have also shown greater penetration through the BBB [10].…”

Section: Discussionmentioning

confidence: 99%

Targeting High Mobility Group Box 1 in Subarachnoid Hemorrhage: A Systematic Review

Muhammad

Chaudhry

Kahlert

et al. 2020

IJMS

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Aneurysmal subarachnoid hemorrhage (aSAH) is a complex and potentially deadly disease. Neurosurgical clipping or endovascular coiling can successfully obliterate ruptured aneurysms in almost every case. However, despite successful interventions, the clinical outcomes of aSAH patients are often poor. The reasons for poor outcomes are numerous, including cerebral vasospasm (CVS), post-hemorrhagic hydrocephalus, systemic infections and delayed cerebral ischemia. Although CVS with subsequent cerebral ischemia is one of the main contributors to brain damage after aSAH, little is known about the underlying molecular mechanisms of brain damage. This review emphasizes the importance of pharmacological interventions targeting high mobility group box 1 (HMGB1)-mediated brain damage after subarachnoid hemorrhage (SAH) and CVS. We searched Pubmed, Ovid medline and Scopus for “subarachnoid hemorrhage” in combination with “HMGB1”. Based on these criteria, a total of 31 articles were retrieved. After excluding duplicates and selecting the relevant references from the retrieved articles, eight publications were selected for the review of the pharmacological interventions targeting HMGB1 in SAH. Damaged central nervous system cells release damage-associated molecular pattern molecules (DAMPs) that are important for initiating, driving and sustaining the inflammatory response following an aSAH. The discussed evidence suggested that HMGB1, an important DAMP, contributes to brain damage during early brain injury and also to the development of CVS during the late phase. Different pharmacological interventions employing natural compounds with HMGB1-antagonizing activity, antibody targeting of HMGB1 or scavenging HMGB1 by soluble receptors for advanced glycation end products (sRAGE), have been shown to dampen the inflammation mediated brain damage and protect against CVS. The experimental data suggest that HMGB1 inhibition is a promising strategy to reduce aSAH-related brain damage and CVS. Clinical studies are needed to validate these findings that may lead to the development of potential treatment options that are much needed in aSAH.

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“…This problem is especially evident for biologicals such as monoclonal antibodies (mAbs) that are relatively large molecules. To overcome the presumed drug delivery obstacle in the brain, many treatment strategies for CNS diseases are directed at disrupting, passing, or bypassing the effective BBB [46,47]. Disruption has been tried chemically, by drugs that influence passive diffusion (e.g., bradykinin, mannitol, regadenoson, and borneol) or active transport mechanisms (e.g., elacridar), or by radiotherapy, ultrasound, or microwaves.…”

Section: Discussionmentioning

confidence: 99%

“…Disruption has been tried chemically, by drugs that influence passive diffusion (e.g., bradykinin, mannitol, regadenoson, and borneol) or active transport mechanisms (e.g., elacridar), or by radiotherapy, ultrasound, or microwaves. Moreover, via viral vectors, nanoparticles, liposomes, exosomes, and transporter or receptor ligands have been tried to bypass the BBB [46,47].…”

Section: Discussionmentioning

confidence: 99%

IC100: A Novel Anti-Asc Monoclonal Antibody Improves Functional Outcomes In An Animal Model Of Multiple Sclerosis

Desu

Plastini

Illiano

et al. 2020

Preprint

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Background The inflammasome adaptor apoptosis-associated speck-like protein containing a CARD (ASC) is involved in immune signaling by bridging the interactions between inflammasome sensors and caspase-1. Strong experimental evidence has shown that ASC-/- mice are protected from disease progression in animal models of multiple sclerosis (MS), suggesting that targeting inflammasome activation via ASC inhibition may be a promising therapeutic strategy in MS. Thus, the goal of our study is to test the efficacy of IC100, a novel humanized antibody targeting ASC, in preventing and/or suppressing disease in the experimental autoimmune encephalomyelitis (EAE) model of MS. Methods We employed the EAE model of MS where disease was induced by immunization of C57BL/6 mice with myelin oligodendrocyte glycoprotein peptide 35-55 (MOG35-55). Mice were treated with vehicle or increasing doses of IC100 (10, 30 and 45 mg/kg) and clinical disease course was evaluated up to 35 days post EAE induction. Immune cell infiltration into the spinal cord and microglia responses were assessed.Results We show that IC100 treatment reduced the severity of EAE when compared to vehicle-treated controls. At a dose of 30 mg/kg, IC100 significantly reduced the number of CD4+ and CD8+ T cells and CD11b+MHCII+ activated myeloid cells entering the spinal cord from the periphery, and reduced the number of total and activated microglia. Conclusions These data indicate that IC100 suppresses the immune-inflammatory response that drives EAE development and progression, thereby identifying ASC as a promising target for the treatment of MS as well as other neurological diseases with a neuroinflammatory component.

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Brain Access of Monoclonal Antibodies as Imaged and Quantified by ⁸⁹Zr-Antibody PET: Perspectives for Treatment of Brain Diseases

Cited by 14 publications

References 12 publications

IC100: a novel anti-ASC monoclonal antibody improves functional outcomes in an animal model of multiple sclerosis

IC100: a novel anti-ASC monoclonal antibody improves functional outcomes in an animal model of multiple sclerosis

Targeting High Mobility Group Box 1 in Subarachnoid Hemorrhage: A Systematic Review

IC100: A Novel Anti-Asc Monoclonal Antibody Improves Functional Outcomes In An Animal Model Of Multiple Sclerosis

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Brain Access of Monoclonal Antibodies as Imaged and Quantified by 89Zr-Antibody PET: Perspectives for Treatment of Brain Diseases

Cited by 14 publications

References 12 publications

IC100: a novel anti-ASC monoclonal antibody improves functional outcomes in an animal model of multiple sclerosis

IC100: a novel anti-ASC monoclonal antibody improves functional outcomes in an animal model of multiple sclerosis

Targeting High Mobility Group Box 1 in Subarachnoid Hemorrhage: A Systematic Review

IC100: A Novel Anti-Asc Monoclonal Antibody Improves Functional Outcomes In An Animal Model Of Multiple Sclerosis

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Product

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Brain Access of Monoclonal Antibodies as Imaged and Quantified by ⁸⁹Zr-Antibody PET: Perspectives for Treatment of Brain Diseases