scholarly journals Insulin Receptor Antibody–Sulfamidase Fusion Protein Penetrates the Primate Blood–Brain Barrier and Reduces Glycosoaminoglycans in Sanfilippo Type A Cells

2014 ◽  
Vol 11 (8) ◽  
pp. 2928-2934 ◽  
Author(s):  
Ruben J. Boado ◽  
Jeff Zhiqiang Lu ◽  
Eric Ka-Wai Hui ◽  
William M. Pardridge
Keyword(s):  
Fusion Protein ◽  
Insulin Receptor ◽  
Blood Brain Barrier ◽  
Type A ◽  
Brain Barrier ◽  
Receptor Antibody ◽  
Blood Brain ◽  
A Cells

scholarly journals Kinetics of Blood–Brain Barrier Transport of Monoclonal Antibodies Targeting the Insulin Receptor and the Transferrin Receptor

2021 ◽  
Vol 15 (1) ◽  
pp. 3
Author(s):  
William M. Pardridge
Keyword(s):  
Fusion Protein ◽  
Mathematical Models ◽  
Insulin Receptor ◽  
Blood Brain Barrier ◽  
Transferrin Receptor ◽  
Brain Barrier ◽  
Luminal Membrane ◽  
Blood Brain ◽  
Kinetics Of ◽  
The Brain

Biologic drugs are large molecule pharmaceuticals that do not cross the blood–brain barrier (BBB), which is formed by the brain capillary endothelium. Biologics can be re-engineered for BBB transport as IgG fusion proteins, where the IgG domain is a monoclonal antibody (MAb) that targets an endogenous BBB transporter, such as the insulin receptor (IR) or transferrin receptor (TfR). The IR and TfR at the BBB transport the receptor-specific MAb in parallel with the transport of the endogenous ligand, insulin or transferrin. The kinetics of BBB transport of insulin or transferrin, or an IRMAb or TfRMAb, can be quantified with separate mathematical models. Mathematical models to estimate the half-time of receptor endocytosis, MAb or ligand exocytosis into brain extracellular space, or receptor recycling back to the endothelial luminal membrane were fit to the brain uptake of a TfRMAb or a IRMAb fusion protein in the Rhesus monkey. Model fits to the data also allow for estimates of the rates of association of the MAb in plasma with the IR or TfR that is embedded within the endothelial luminal membrane in vivo. The parameters generated from the model fits can be used to estimate the brain concentration profile of the MAb over time, and this brain exposure is shown to be a function of the rate of clearance of the antibody fusion protein from the plasma compartment.

Inhibition of Notch and tumor regression

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14623-e14623
Author(s):  
A. A. Epenetos ◽  
C. Kousparou ◽  
S. Stylianou
Keyword(s):  
Stem Cells ◽  
Fusion Protein ◽  
Notch Signaling ◽  
Blood Brain Barrier ◽  
Tumor Regression ◽  
The Self ◽  
Brain Barrier ◽  
Self Renewal ◽  
Blood Brain ◽  
Repeat Administration

e14623 Background: Notch signaling is an evolutionary-conserved pathway in vertebrates and invertebrates which is involved many developmental processes, including cell fate decisions, apoptosis, proliferation, and stem-cell self renewal. There is increasing evidence that the same molecular pathways regulating the self renewal of stem cells are also being employed in cancer progression. The Notch signal transduction pathway has been implicated in the self-renewal of stem cells in hematopoietic, skin, neural, germ and breast tissue. Increasing evidence suggests that the Notch signaling pathway is frequently up regulated in many forms of cancer including acute T-cell lymphoblastic leukemia, cervical, prostate, lung, breast and others. Thus,inhibition of the pathway could provide a novel treatment of cancer and cancer stem cells. Methods: We have genetically engineered a fusion protein, consisting of the Drosophila transcription factor Antennapedia (ANTP) and with the truncated version of Mastermind-like (MAML) that behaves in a dominant negative (DN) fashion and inhibits Notch activation (ANTP/DN MAML, TR4). This novel fusion protein has been tested for its ability to target tumor cells in vitro and in vivo. Results: Our data show that ANTP/DN MAML fusion protein, TR4 contains signals for proper cell targeting, internalization and nuclear transport. Furthermore, TR4 inhibits human mammary and colon xenograft tumor growth and metastases in immuno deficient mice.TR4 presence and activity was also detected in the brains of treated animals demonstrating that TR4 can cross the blood-brain barrier and potentially eliminate brain tumors and metastases, unlike other anticancer drugs and biological such as monoclonal antibodies that cannot cross the blood brain barrier. TR4 was found to be non- immunogenic following repeat administration in healthy animals. At very high doses (>10x therapeutic dose) it caused anorexia and weight loss in mice. Conclusions: The TR4 protein, a Notch inhibitor, can induce tumor regression and resolution of breast and colon cancer xenografts. It is non- immunogenic following repeat administration and has acceptable toxicity profile. No significant financial relationships to disclose.

GDNF fusion protein for targeted-drug delivery across the human blood–brain barrier

2008 ◽  
Vol 100 (2) ◽  
pp. 387-396 ◽  
Author(s):  
Ruben J. Boado ◽  
Yun Zhang ◽  
Yufeng Zhang ◽  
Yuntao Wang ◽  
William M. Pardridge
Keyword(s):  
Drug Delivery ◽  
Fusion Protein ◽  
Blood Brain Barrier ◽  
Human Blood ◽  
Targeted Drug Delivery ◽  
Brain Barrier ◽  
Blood Brain ◽  
Targeted Drug

scholarly journals Trafficking of Gold Nanoparticles Coated with the 8D3 Anti-Transferrin Receptor Antibody at the Mouse Blood–Brain Barrier

2015 ◽  
Vol 12 (11) ◽  
pp. 4137-4145 ◽  
Author(s):  
Itsaso Cabezón ◽  
Gemma Manich ◽  
Raquel Martín-Venegas ◽  
Antoni Camins ◽  
Carme Pelegrí ◽  
...  
Keyword(s):  
Gold Nanoparticles ◽  
Blood Brain Barrier ◽  
Transferrin Receptor ◽  
Brain Barrier ◽  
Mouse Blood ◽  
Receptor Antibody ◽  
Blood Brain
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