CALABASAS, CA, United States
CALABASAS, CA, United States

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Provided herein are compositions and related methods for delivering an IgG-decoy receptor to the CNS. The methods include systemic administration of a bifunctional decoy receptor-BBB receptor antibody fusion antibody comprising a receptor extracellular domain (ECD) covalently linked to an antibody to a receptor expressed on the surface of the blood-brain barrier (BBB receptor). In some embodiments, the compositions described herein are administered to treat a subject suffering from a CNS condition.


Patent
Armagen Technologies, Inc. | Date: 2017-01-18

The invention provides compositions, methods, and kits for increasing transport of agents across the blood brain barrier while allowing their activity once across the barrier to remain substantially intact. The agents are transported across the blood brain barrier via one or more endogenous receptor-mediated transport systems. In some embodiments the agents are therapeutic, diagnostic, or research agents.


Patent
Armagen Technologies, Inc. | Date: 2017-01-03

Provided herein are methods and compositions for treating a subject suffering from a deficiency in -L-Iduronidase in the CNS. The methods include systemic administration of a bifunctional fusion antibody comprising an antibody to a human insulin receptor and an -L-Iduronidase. A therapeutically effective systemic dose is based on the specific CNS uptake characteristics of human insulin receptor antibody--L-Iduronidase fusion antibodies as described herein.


Pardridge W.M.,Armagen Technologies, Inc.
Expert Opinion on Drug Delivery | Year: 2015

Introduction: Biologic drugs are large molecules that do not cross the blood-brain barrier (BBB). Brain penetration is possible following the re-engineering of the biologic drug as an IgG fusion protein. The IgG domain is a MAb against an endogenous BBB receptor such as the transferrin receptor (TfR). The TfRMAb acts as a molecular Trojan horse to ferry the fused biologic drug into the brain via receptor-mediated transport on the endogenous BBB TfR. Areas covered: This review discusses TfR isoforms, models of BBB transport of transferrin and TfRMAbs, and the genetic engineering of TfRMAb fusion proteins, including BBB penetrating IgG-neurotrophins, IgG-decoy receptors, IgG-lysosomal enzyme therapeutics and IgG-avidin fusion proteins, as well as BBB transport of bispecific antibodies formed by fusion of a therapeutic antibody to a TfRMAb targeting antibody. Also discussed are quantitative aspects of the plasma pharmacokinetics and brain uptake of TfRMAb fusion proteins, as compared to the brain uptake of small molecules, and therapeutic applications of TfRMAb fusion proteins in mouse models of neural disease, including Parkinson's disease, stroke, Alzheimer's disease and lysosomal storage disorders. The review covers the engineering of TfRMAb-avidin fusion proteins for BBB targeted delivery of biotinylated peptide radiopharmaceuticals, low-affinity TfRMAb Trojan horses and the safety pharmacology of chronic administration of TfRMAb fusion proteins. Expert opinion: The BBB delivery of biologic drugs is possible following re-engineering as a fusion protein with a molecular Trojan horse such as a TfRMAb. The efficacy of this technology will be determined by the outcome of future clinical trials. © 2014 Informa UK, Ltd.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 1.03M | Year: 2015

DESCRIPTION provided by applicant Type IIIA Mucopolysaccharidosis MPS also known as Sanfilippo A syndrome is a genetic disease that affects the lysosomal enzyme N sulfoglucosamine sulfohydrolase SGSH also called sulfamidase Consequently patients with MPS IIIA develop extensive lysosomal storage product accumulation in the brain Children born with MPS IIIA develop multiple brain disorders including mental retardation and hydrocephalus The current therapy for lysosomal storage disorders is Enzyme Replacement Therapy ERT with the recombinant human enzyme However ERT will not treat the brain of MPS IIIA because SGSH does not cross the blood brain barrier BBB The present work will continue work on the development of a new treatment of the brain of MPS IIIA which is a genetically engineered biopharmaceutical fusion protein named AGT The SGSH is genetically fused to a BBB molecular Trojan horse which is a genetically engineered peptidomimetic monoclonal antibody MAb against an endogenous BBB peptide receptor the human insulin receptor HIR The human SGSH is fused to the heavy chain of the HIRMAb to create a new chemical entity called the HIRMAb SGSH fusion protein Phase I studies show the HIRMAb SGSH fusion protein could be engineered and expressed by stably transfected host cells The fusion protein retained high affinity binding to the HIR and retained high SGSH enzyme activity The proposed phase II work will develop a manufacturing plan that can be replicated for future GMP manufacturing The AGT produced in phase II will be evaluated for safety toxicology and pharmacokinetics in a Rhesus monkey dose finding study The completion of this work will enable entry of the AGT drug development program into GLP toxicology and GMP manufacturing required for submission of an IND to begin treatment of the brain in patients with MPS IIIA PUBLIC HEALTH RELEVANCE Mucopolysacchridosis Type IIIA or Sanfilippo A Syndrome is an inherited condition where patients develop severe brain abnormalities owing to the genetic defect in the gene encoding the lysosomal enzyme N sulfoglucosamine sulfohydrolase SGSH Enzyme replacement therapy ERT is not effective for the brain because the SGSH does not cross the blood brain barrier BBB This research will develop a new treatment for the brain in patients with MPSIIIA which involves the re engineering of human SGSH as an IgG fusion protein that crosses the human BBB


The invention provides diagnostic and therapeutic macromolecular compositions that cross the blood-brain barrier, in some embodiments in both directions, while allowing their activity to remain substantially intact once across the barrier. Also provided are methods for using such compositions in the diagnosis or treatment of CNS disorders such as Alzheimers disease.


Patent
Armagen Technologies, Inc. | Date: 2016-03-23

Provided herein are methods and compositions for treating a subject suffering from a deficiency in -L-Iduronidase in the CNS. The methods include systemic administration of a bifunctional fusion antibody comprising an antibody to a human insulin receptor and an -L-Iduronidase. A therapeutically effective systemic dose is based on the specific CNS uptake characteristics of human insulin receptor antibody--L-Iduronidase fusion antibodies as described herein.


Provided herein are methods and compositions for treating a subject suffering from an enzyme deficiency in the central nervous system (CNS). The bifunctional fusion antibody provided herein comprise an antibody to an endogenous blood brain barrier (BBB) receptor and an enzyme deficient in mucopolysaccharidosis IIIB (MPS-IIIB). The fusion antibodies provided herein comprise alpha-N-acetylgulcosaminidase (NAGLU). The methods of treating an enzyme deficiency in the CNS comprise systemic administration of a fusion antibody provided herein.


Patent
Armagen Technologies, Inc. | Date: 2015-01-27

Provided herein are methods and compositions for treating a subject suffering from a deficiency in -L-Iduronidase in the CNS. The methods include systemic administration of a bifunctional fusion antibody comprising an antibody to a human insulin receptor and an -L-Iduronidase. A therapeutically effective systemic dose is based on the specific CNS uptake characteristics of human insulin receptor antibody--L-Iduronidase fusion antibodies as described herein.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 152.14K | Year: 2014

DESCRIPTION (provided by applicant): Mucopolysaccharidosis (MPS) Type IIIA, also called Sanfilippo A syndrome, is a genetic disease caused by mutations in the gene encoding the lysosomal enzyme, N-sulfoglucosamine sulfohydrolase (SGSH), also called sulfamidase. Symptoms including neurodegeneration and mental retardation appear during infancy or childhood; and early death occurs due to organ damage in the brain. Enzyme replacement therapy (ERT) cannot treat the brain, since recombinant SGSH does not cross the blood-brain barrier (BBB). Accordingly, clinical trials on the treatment of children with MPSIIIA with intravenous recombinant SGSH have been abandoned. The present work will re-engineer human SGSH to enable transport across the BBB using a molecular Trojan horse technology. A molecular Trojan horse is a genetically engineered peptidomimetic monoclonal antibody (MAb) against an endogenous BBB peptide receptor, such as the human insulin receptor (HIR). The human SGSH is fused to the heavy chain of th

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