Antibody Approaches To Treat Brain Diseases

Neves, Vera; Aires-da-Silva, Frederico; Côrte‐Real, Sofia; Castanho, Miguel A. R. B.

doi:10.1016/j.tibtech.2015.10.005

Cited by 57 publications

(53 citation statements)

References 72 publications

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“…These translocation mechanisms are fundamental for the uptake of essential substances to maintain brain homeostasis. They can be classified into: (1) CMT, which are responsible for the cross of glucose (glucose transporter-GLUT1), amino acids (large neutral amino acid transporter-LAT1, and cationic amino acid transporter-CAT1), and nucleosides (nucleobase transporter-NBT); (2) RMT, fundamental for large molecules translocation, such as transferrin (transferrin receptor-TfR), insulin (insulin receptor-IR), low-density lipoprotein (lipoprotein receptor-mediated protein-LRP), leptin (leptin receptor-LEPR), and fragment crystallizable (Fc) fragment of immunoglobulin G (IgG) (Fc fragment of IgG receptor transporter α-FCGRT); and finally, (3) AMT that drives albumin and other plasma proteins to brain [44].…”

Section: Physiological Approachmentioning

confidence: 99%

Antibodies for the Treatment of Brain Metastases, a Dream or a Reality?

et al. 2020

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The incidence of brain metastases (BM) in cancer patients is increasing. After diagnosis, overall survival (OS) is poor, elicited by the lack of an effective treatment. Monoclonal antibody (mAb)-based therapy has achieved remarkable success in treating both hematologic and non-central-nervous system (CNS) tumors due to their inherent targeting specificity. However, the use of mAbs in the treatment of CNS tumors is restricted by the blood–brain barrier (BBB) that hinders the delivery of either small-molecules drugs (sMDs) or therapeutic proteins (TPs). To overcome this limitation, active research is focused on the development of strategies to deliver TPs and increase their concentration in the brain. Yet, their molecular weight and hydrophilic nature turn this task into a challenge. The use of BBB peptide shuttles is an elegant strategy. They explore either receptor-mediated transcytosis (RMT) or adsorptive-mediated transcytosis (AMT) to cross the BBB. The latter is preferable since it avoids enzymatic degradation, receptor saturation, and competition with natural receptor substrates, which reduces adverse events. Therefore, the combination of mAbs properties (e.g., selectivity and long half-life) with BBB peptide shuttles (e.g., BBB translocation and delivery into the brain) turns the therapeutic conjugate in a valid approach to safely overcome the BBB and efficiently eliminate metastatic brain cells.

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Section: Physiological Approachmentioning

confidence: 99%

Antibodies for the Treatment of Brain Metastases, a Dream or a Reality?

et al. 2020

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“…As tau aggregates fast after cytoplasmic entry, the rapid recruitment of TRIM21 to incoming antibody:tau complexes are likely crucial for prevention. This discovery may foster development of new therapeutic approaches where delivery strategies for antibodies through the blood-brain barrier could be combined with targeting of extracellular tau to TRIM21 (20,87,88).…”

Section: Implications For Therapymentioning

confidence: 99%

TRIM21—From Intracellular Immunity to Therapy

et al. 2019

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Tripartite motif containing-21 (TRIM21) is a cytosolic ubiquitin ligase and antibody receptor that provides a last line of defense against invading viruses. It does so by acting as a sensor that intercepts antibody-coated viruses that have evaded extracellular neutralization and breached the cell membrane. Upon engagement of the Fc of antibodies bound to viruses, TRIM21 triggers a coordinated effector and signaling response that prevents viral replication while at the same time inducing an anti-viral cellular state. This dual effector function is tightly regulated by auto-ubiquitination and phosphorylation. Therapeutically, TRIM21 has been shown to be detrimental in adenovirus based gene therapy, while it may be favorably utilized to prevent tau aggregation in neurodegenerative disorders. In addition, TRIM21 may synergize with the complement system to block viral replication as well as transgene expression. TRIM21 can also be utilized as a research tool to deplete specific proteins in cells and zebrafish embryos. Here, we review our current biological understanding of TRIM21 in light of its versatile functions.

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“…Antibodies used for targeted treatment always include the variable domain, with different portions of the remaining structure [reviewed in (Neves et al . )]. The use of antibodies in the treatment of brain disorders is limited by the permeability of the blood–brain barrier.…”

Section: Therapeutic Modalitiesmentioning

confidence: 99%

“…An antibody molecule comprises two heavy and two light chains connected via disulfide bridges, both containing a variable domain responsible for recognition of an antigen. Antibodies used for targeted treatment always include the variable domain, with different portions of the remaining structure [reviewed in (Neves et al 2016)]. The use of antibodies in the treatment of brain disorders is limited by the permeability of the blood-brain barrier.…”

Section: Antibodiesmentioning

confidence: 99%

Models for discovery of targeted therapy in genetic epileptic encephalopathies

Maljevic

Reid

Petrou

2017

Journal of Neurochemistry

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Epileptic encephalopathies are severe disorders emerging in the first days to years of life that commonly include refractory seizures, various types of movement disorders, and different levels of developmental delay. In recent years, many de novo occurring variants have been identified in individuals with these devastating disorders. To unravel disease mechanisms, the functional impact of detected variants associated with epileptic encephalopathies is investigated in a range of cellular and animal models. This review addresses efforts to advance and use such models to identify specific molecular and cellular targets for the development of novel therapies. We focus on ion channels as the best-studied group of epilepsy genes. Given the clinical and genetic heterogeneity of epileptic encephalopathy disorders, experimental models that can reflect this complexity are critical for the development of disease mechanisms-based targeted therapy. The convergence of technological advances in gene sequencing, stem cell biology, genome editing, and high throughput functional screening together with massive unmet clinical needs provides unprecedented opportunities and imperatives for precision medicine in epileptic encephalopathies.

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Antibody Approaches To Treat Brain Diseases

Cited by 57 publications

References 72 publications

Antibodies for the Treatment of Brain Metastases, a Dream or a Reality?

Antibodies for the Treatment of Brain Metastases, a Dream or a Reality?

TRIM21—From Intracellular Immunity to Therapy

Models for discovery of targeted therapy in genetic epileptic encephalopathies

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