The blood-brain barrier limits the therapeutic efficacy of antibody drug conjugates in glioblastoma

2021 ◽  
Author(s):  
Roger Abounader ◽  
David Schiff
Keyword(s):  
Blood Brain Barrier ◽  
Therapeutic Efficacy ◽  
Brain Barrier ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Blood Brain ◽  
Antibody Drug

scholarly journals Anti-transferrin receptor antibody and antibody-drug conjugates cross the blood-brain barrier.

1991 ◽  
Vol 88 (11) ◽  
pp. 4771-4775 ◽  
Author(s):  
P. M. Friden ◽  
L. R. Walus ◽  
G. F. Musso ◽  
M. A. Taylor ◽  
B. Malfroy ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Transferrin Receptor ◽  
Brain Barrier ◽  
Antibody Drug Conjugates ◽  
Receptor Antibody ◽  
Drug Conjugates ◽  
Blood Brain ◽  
Antibody Drug

scholarly journals Discovery of a Highly Conserved Peptide in the Iron Transporter Melanotransferrin that Traverses an Intact Blood Brain Barrier and Localized in Neural Cells

2021 ◽  
Vol 15 ◽  
Author(s):  
Chaahat S. B. Singh ◽  
Brett A. Eyford ◽  
Thomas Abraham ◽  
Lonna Munro ◽  
Kyung Bok Choi ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Soluble Form ◽  
Neural Cells ◽  
Amino Acid Peptide ◽  
Drug Conjugates ◽  
Blood Brain ◽  
Targeting Delivery ◽  
The Brain ◽  
Effective Carrier

The blood-brain barrier (BBB) hinders the distribution of therapeutics intended for treatment of diseases of the brain. Our previous studies demonstrated that that a soluble form of melanotransferrin (MTf; Uniprot P08582; also known as p97, MFI2, and CD228), a mammalian iron-transport protein, is an effective carrier for delivery of drug conjugates across the BBB into the brain and was the first BBB targeting delivery system to demonstrate therapeutic efficacy within the brain. Here, we performed a screen to identify peptides from MTf capable of traversing the BBB. We identified a highly conserved 12-amino acid peptide, termed MTfp, that retains the ability to cross the intact BBB intact, distributes throughout the parenchyma, and enter endosomes and lysosomes within neurons, astrocytes and microglia in the brain. This peptide may provide a platform for the transport of therapeutics to the CNS, and thereby offers new avenues for potential treatments of neuropathologies that are currently refractory to existing therapies.

scholarly journals ATPS-46PRECLINICAL THERAPEUTIC EFFICACY OF A NOVEL BLOOD-BRAIN BARRIER-PENETRANT DUAL PI3K/MTOR INHIBITOR WITH PREFERENTIAL RESPONSE IN PI3K/PTEN MUTANT GLIOMA

2015 ◽  
Vol 17 (suppl 5) ◽  
pp. v28.2-v28
Author(s):  
Dimpy Koul ◽  
Shuzhen Wang ◽  
Norihiko Saito ◽  
Siyuan Zheng ◽  
Shaofang Wu ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Therapeutic Efficacy ◽  
Mtor Inhibitor ◽  
Brain Barrier ◽  
Blood Brain

scholarly journals Antibody-Drug Conjugates: Patient and Treatment Selection

2020 ◽  
pp. 105-114
Author(s):  
Shalini Makawita ◽  
Funda Meric-Bernstam
Keyword(s):  
Patient Selection ◽  
Therapeutic Efficacy ◽  
Antigen Expression ◽  
Therapeutic Modality ◽  
Intratumor Heterogeneity ◽  
Target Antigen ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
The Impact ◽  
Antibody Drug

Antibody-drug conjugates (ADCs) are a promising drug platform designed to enhance the therapeutic index and minimize the toxicity of anticancer agents. ADCs have experienced substantial progress and technological growth over the past decades; however, several challenges to patient selection and treatment remain. Methods to optimally capture all patients who may benefit from a particular ADC are still largely unknown. Although target antigen expression remains a biomarker for patient selection, the impact of intratumor heterogeneity on antigen expression, as well as the dynamic changes in expression with treatment and disease progression, are important considerations in patient selection. Better understanding of these factors, as well as minimum levels of target antigen expression required to achieve therapeutic efficacy, will enable further optimization of selection strategies. Other important considerations include understanding mechanisms of primary and acquired resistance to ADCs. Ongoing efforts in the design of its constituent parts to possess the intrinsic ability to overcome these mechanisms, including use of the “bystander effect” to enhance efficacy in heterogeneous or low target antigen-expressing tumors, as well as modulation of the chemical and immunophenotypic properties of antibodies and linker molecules to improve payload sensitivity and therapeutic efficacy, are under way. These strategies may also lead to improved safety profiles. Similarly, combination strategies using ADCs with other cytotoxic or immunomodulatory agents are also under development. Great strides have been made in ADC technology. With further refinements, this therapeutic modality has the potential to make an important clinical impact on a wider range of tumor types.

Therapeutic efficacy of multiagent chemotherapy with drug delivery enhancement by blood-brain barrier modification in glioblastoma

Neurosurgery ◽  
1986 ◽  
Vol 19 (4) ◽  
pp. 573???82 ◽  
Author(s):  
E A Neuwelt ◽  
J Howieson ◽  
E P Frenkel ◽  
H D Specht ◽  
R Weigel ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Blood Brain Barrier ◽  
Therapeutic Efficacy ◽  
Brain Barrier ◽  
Blood Brain ◽  
Multiagent Chemotherapy

scholarly journals Preclinical therapeutic efficacy of a novel blood-brain barrier-penetrant dual PI3K/mTOR inhibitor with preferential response in PI3K/PTEN mutant glioma

Oncotarget ◽  
2017 ◽  
Vol 8 (13) ◽  
pp. 21741-21753 ◽  
Author(s):  
Dimpy Koul ◽  
Shuzhen Wang ◽  
Shaofang Wu ◽  
Norihiko Saito ◽  
Siyuan Zheng ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Therapeutic Efficacy ◽  
Mtor Inhibitor ◽  
Brain Barrier ◽  
Blood Brain

Novel Drug Delivery System for Curcumin: Implementation to Improve Therapeutic Efficacy against Neurological Disorders

2021 ◽  
Vol 24 ◽  
Author(s):  
Roohi Mohi-ud-din ◽  
Reyaz Hassan Mir ◽  
Taha Umair Wani ◽  
Abdul Jalil Shah ◽  
Ishtiyaq Mohi-Ud-Din ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Therapeutic Efficacy ◽  
Therapeutic Potential ◽  
Polymeric Nanoparticles ◽  
Curcuma Longa ◽  
Brain Barrier ◽  
Barrier Methods ◽  
Blood Brain ◽  
Toxicological Studies ◽  
Novel Drug

Background: Curcumin, a hydrophobic polyphenolic compound present in Curcuma longa Linn. (Turmeric), has been used to improve various neurodegenerative conditions, including Amyotrophic lateral sclerosis, Multiple Sclerosis, Parkinson's disease, Prion disease, stroke, anxiety, depression, and ageing. However, the blood-brain barrier (BBB) impedes the delivery of curcumin to the brain, as a result, limits its therapeutic potential. Objective/Aim: This review summarises the recent advances towards the therapeutic efficacy of curcumin along with various novel strategies to overcome its poor bioavailability across the blood-brain barrier. Methods: The collection of data for the compilation of this review work was searched in PubMed Scopus, Google Scholar, and Science Direct. Result: Various approaches have been opted to expedite the delivery of curcumin across the blood-brain barrier, including liposomes, micelles, polymeric nanoparticles, exosomes, dual targeting Nanoparticles etc. Conclusion: The review also summarises the numerous toxicological studies and the role of curcumin in CNS disorders.

scholarly journals Construction of homogeneous antibody–drug conjugates using site-selective protein chemistry

2016 ◽  
Vol 7 (5) ◽  
pp. 2954-2963 ◽  
Author(s):  
Padma Akkapeddi ◽  
Saara-Anne Azizi ◽  
Allyson M. Freedy ◽  
Pedro M. S. D. Cal ◽  
Pedro M. P. Gois ◽  
...  
Keyword(s):  
Therapeutic Efficacy ◽  
Protein Chemistry ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Drug Conjugation ◽  
Selective Chemical ◽  
Site Selective ◽  
Antibody Drug

The use of site-selective chemical drug-conjugation strategies enables the construction of antibody–drug conjugates (ADCs) with superior therapeutic efficacy.”

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