ArmaGen Technologies-Enabling Biotechnology for the Brain

December 8, 2011. ArmaGen granted 3 U.S. patents on IgG-neurotrophin fusion proteins for targeted brain delivery. Three new patents on IgG-neurotrophin fusion proteins for targeted brain drug delivery across the human blood-brain barrier (BBB) have been issued or allowed by the U.S. Patent Office. The claims are broad and cover any immunoglobulin targeting any endogenous BBB receptor transporter, and 17 neurotrophins, including erythropoietin (EPO) and glial derived neurotrophic factor (GDNF). Over 100 claims have been allowed covering the compositions of IgG-neurotrophin fusion proteins, methods of use, treatment of neurological disease, expression plasmid DNA, and manufacturing. Neurotrophins cause neuroprotection of brain cells in multiple acute and chronic brain diseases, including stroke, brain trauma, Alzheimer's disease, and Parkinson's disease. In addition, certain neurotrophins may also prove to be efficacious new drugs for the treatment of depression and affective disorders. However, neurotrophin drug development is difficult, because neurotrophins are large molecule drugs that do not cross the BBB. ArmaGen's new patent portfolio describes the re-engineering of neurotrophins as brain penetrating IgG-neurotrophin fusion proteins. The IgG part of the fusion protein is a monoclonal antibody against an endogenous BBB receptor transporter, which acts as a molecular Trojan horse to ferry the fused neurotrophin across the BBB, and into brain.

August 12, 2011. ArmaGen treats experimental Parkinson's with first brain-penetrating biologic TNF-Inhibitor. Parkinson's disease (PD) and Alzheimer's disease (AD) are chonic inflammatory conditions of the brain mediated in part by tumor necrosis factor (TNF)-alpha. TNF-alpha action in peripheral tissues is blocked by the biologic TNF-Inhibitors (TNFI), such as adalimumab, infliximab, or etanercept. However, the biologic TNFIs cannot be developed for brain conditions such as PD or AD, because these large molecule drugs do not cross the blood-brain barrier (BBB). AGT-110, the first BBB-penetrating biologic TNFI, was engineered by fusion of the extracellular domain of the Type II human TNF receptor (TNFR) to a genetically engineered monoclonal antibody (MAb) against the human insulin receptor (HIR). The HIRMAb acts as a molecular Trojan horse to ferry the TNFR decoy receptor across the BBB. The HIRMAb-TNFR fusion protein rapidly penetrates the brain of the Rhesus monkey, with a brain uptake of >3% of injected dose, whereas there is no BBB transport of etanercept (2010 Journal of Biotechnology). The mouse-specific homologue of AGT-110 was engineered by fusion of the TNFR decoy receptor to a MAb against the mouse transferrin receptor (TfR), designated the cTfRMAb-TNFR fusion protein, as described in the 2011 Drug Metabolism and Disposition. Now, the cTfRMAb-TNFR fusion protein is shown to be neuroprotective in a mouse model of experimental PD following chronic intravenous (IV) treatment. In contrast, chronic IV treatment with etanercept had no therapeutic effect in PD, because etanercept does not cross the BBB. Treatment of mice with experimental PD resulted in an improvement in 3 assays of neuro-behavior, a 130% increase in striatal tyrosine hydroxylase (TH) enzyme activity, and an increase in immunoreactive TH in the striatum. The work is reported in the 2011 Journal of Pharmacology and Experimental Therapeutics. The work shows that the biologic TNFIs can be developed as brain drugs, providing the biologic TNFI is re-engineered as a fusion protein with a BBB molecular Trojan horse.

June 16, 2011. ArmaGen treats brain of Hurler mouse with Trojan horse-enzyme fusion protein. Adult Hurler mice, a model of Type I Mucopolysaccharidosis (MPS), show reduction in lysosomal inclusion bodies in brain after an 8-week course of twice a week intravenous injections of 1 mg/kg of an IgG-lysosomal enzyme fusion protein. The biopharmaceutical is formed by fusion of the mature murine iduronidase (IDUA) lysosomal enzyme to the heavy chain of a chimeric monoclonal antibody (MAb) against the murine transferrin receptor (TfR). The TfRMAb crosses the blood-brain barrier (BBB) via transport on the endogenous TfR, and acts as a molecular Trojan horse to ferry into brain the fused IDUA therapeutic. The TfRMAb-IDUA fusion protein is bi-functional and binds the murine TfR with high affinity (KD=0.67 nM), and has high IDUA enzyme activity (776 units/ug protein). Treatment caused a 73% decrease in brain cell lysosomal inclusion bodies, and also reduced glycosoaminoglycan levels in peripheral tissues. The study shows that the lysosomal inclusion bodies in the brain can be reversed even in aged 6-8 month old Hurler mice with intravenous enzyme replacement therapy, providing the enzyme is re-engineered to cross the BBB with the molecular Trojan horse technology. The study is reported in the 2011 Molecular Pharmaceutics.

March 16, 2011. ArmaGen engineers brain-penetrating IDS for treatment of the brain in MPS Type II. Type II Mucopolysaccharidosis (MPS), Hunter's syndrome, is caused by mutations in the gene encoding the lysosomal enzyme iduronate 2-sulfatase (IDS). Most patients with MPS-II have brain pathology, and recombinant IDS does not treat the brain, because IDS does not cross the blood-brain barrier (BBB). Human IDS was re-engineered as an IgG-IDS fusion protein, AGT-182. The IgG part of the fusion protein is a genetically engineered monoclonal antibody (MAb) against the human insulin receptor (HIR). AGT-182 is a bi-functional protein, which both binds the HIR with high affinity (KD <1 nM), and expresses high IDS enzyme activity. The HIRMAb part of the fusion protein acts as a molecular Trojan horse, which carries the fused IDS across the blood-brain barrier and across the neuronal cell membrane via receptor-mediated transport on the endogenous insulin receptor. The HIRMAb-IDS fusion protein (AGT-182) is triaged to the lysosomal compartment in Hunter fibroblasts, and normalizes glycosoaminoglycan levels. The HIRMAb-IDUS fusion protein rapidly penetrates the BBB in the Rhesus monkey following intravenous administration. The work is published in the 2011 Biotechnology & Bioengineering.

January 14, 2011. ArmaGen engineers brain-penetrating amyloid antibody for Alzheimer's disease. Alzheimer's disease (AD) is caused by the deposition of amyloid plaque in brain, and the leading plaque disaggregation therapeutic is the anti-amyloid antibody (AAA). Plaque disaggregation is caused by physical contact between the AAA and the plaque. However, the plaque in brain is behind the blood-brain barrier (BBB), and the AAA does not penetrate the brain in the absence of BBB disruption. Another problem with the current class of AAA biologics is that these drugs have prolonged blood mean residence times (MRT) of 30 days, and cause large and sustained elevations in blood concentrations of amyloid peptides, which are toxic molecules. ArmaGen has engineered AGT-160, which is a brain penetrating AAA for AD (Biotechnology & Bioengineering, 2010). The brain-penetrating AAA is also rapidly removed from blood with a MRT of <3 hours. The efficacy of the brain penetrating AAA was tested in a transgenic AD mouse model. A single chain Fv (ScFv) form of the AAA was engineered and fused to a genetically engineered monoclonal antibody (MAb) against the mouse transferrin receptor (TfR). The TfRMAb-ScFv fusion protein was administered twice-weekly to AD mice for 12 weeks by IV injection at a dose of 1 mg/kg. Treatment caused a 40% decrease in the brain concentration of Abeta amyloid peptide, but caused no elevation in Abeta amyloid peptide in blood, and caused no cerebral micro-hemorrhage (Molecular Pharmaceutics, 2011). AAAs that are re-engineered to cross the BBB can disaggregate plaque without causing toxic side effects associated with high blood amyloid peptide levels.

2010

November 5, 2010. ArmaGen re-engineers erythropoietin for stroke. Erythropoietin (EPO) is a potent neuroprotective agent, which could be developed for treatment of acute stroke. However, EPO does not cross the blood-brain barrier (BBB), and the BBB is intact in the early hours after stroke when neuroprotection is still possible. AGT-115 is a re-engineered form of human EPO that crosses the BBB via receptor-mediated transport. EPO is fused to a genetically engineered monoclonal antibody (MAb) against the human insulin receptor (HIR). The HIRMAb acts as a molecular Trojan horse to ferry the fused EPO across the BBB following intravenous injection. The engineering and validation of the HIRMAb-EPO fusion protein was reported in the 2010 Journal of Pharmacology & Experimental Therapeutics. The HIRMAb-EPO fusion protein was shown to be rapidly transported across the BBB in the Rhesus monkey, and to have a pharmacokinetics profile that reduces EPO biological activity in peripheral tissues. The HIRMAb-EPO fusion protein reduced the stroke volume and neural deficit by 98% following injection into the brain of rats with a permanent middle cerebral artery occlusion (MCAO), as reported in the 2010 Brain Research. In the rat MCAO model, the HIRMAb-EPO fusion protein was injected into the brain, because the HIRMAb part of the fusion protein does not recognize the rat insulin receptor. To enable neuroprotection following intravenous injection in rodent stroke models, ArmaGen has engineered a surrogate Trojan horse that is active at the BBB in the mouse. The genetic engineering, brain uptake, and pharmacokinetics of the mouse Trojan horse-EPO fusion protein are described in the 2010 Molecular Pharmaceutics. The intravenous injection of the Trojan horse-EPO fusion protein in the permanent MCAO model in the mouse caused a 81% reduction in the stroke volume, which was associated with a 78% reduction in neural deficit, as reported in the 2011 Brain Research.

August 17, 2010. ArmaGen completes Pre-IND Meeting with FDA for AGT-181. ArmaGen has completed a Pre-IND Meeting with the FDA for a phase I-II trial of intravenous AGT-181 for treatment of the brain in Mucopolysaccharidosis (MPS) Type I, also known as Hurler's syndrome. MPS-I is a lysosomal storage disorder that affects the brain and spinal cord. Standard Enzyme Replacement Therapy (ERT) does not treat the brain, because the recombinant enzyme does not cross the blood-brain barrier (BBB). The lysosomal enzyme missing in MPS-I is iduronidase (IDUA). AGT-181 is a re-engineered form of human IDUA, where the lysosomal enzyme is fused to an IgG. The IgG is a genetically engineered monoclonal antibody (MAb) to the human insulin receptor (HIR). The HIRMAb part of the AGT-181 fusion protein acts as a molecular Trojan horse to ferry the fused IDUA across the BBB and across the target cell membrane, by binding to the endogenous insulin receptor. A dose-ranging study in 8 Rhesus monkeys demonstrated an excellent AGT-181 safety profile, as described in the 2009 Journal of Biotechnology. ArmaGen will now perform GLP toxicology, safety pharmacology, and tissue cross-reactivity investigations to support the IND of AGT-181 for the treatment of the brain in MPS-I. ArmaGen manufactures the Toxicology Lot and Reference Standard for AGT-181 at its manufacturing facility in Santa Monica, CA.

May 17, 2010. ArmaGen re-engineers erythropoietin for brain penetration. Human erythropoietin (EPO) is a potent neuroprotective agent for multiple brain disorders, including stroke, brain and spinal cord injury, and Parkinson's disease. However, EPO does not cross the blood-brain barrier (BBB). ArmaGen has successfully re-engineered human EPO as an IgG fusion protein that penetrates the primate brain following intravenous (IV) administration. Human EPO is fused to a genetically engineered monoclonal antibody (MAb) to the human insulin receptor (HIR). The HIRMAb acts as a molecular Trojan horse to ferry the EPO across the BBB via transport on the endogenous BBB insulin receptor. The HIRMAb-EPO fusion protein is a dual receptor specific protein with low nM binding constants for both the human EPO receptor and the human insulin receptor. The HIRMAb part of the HIRMAb-EPO fusion protein cross-reacts with the Rhesus monkey insulin receptor. The HIRMAb-EPO fusion protein rapidly penetrates the BBB in vivo in the adult Rhesus monkey following IV administration, whereas EPO alone is not transported across the BBB. The brain uptake of the HIRMAb-EPO fusion protein in the Rhesus monkey is high, 2% injected dose/brain, and comparable to small molecules. The pharmacokinetics (PK) of the HIRMAb-EPO fusion protein differ markely from the PK of EPO, which minimizes any effect of the fusion protein on bone marrow. EPO-driven neuroprotection in brain is now possible with intravenous administration of the HIRMAb-EPO fusion protein at doses that may minimal effects on erthyropoiesis. The work is published in the June, 2010 issue of the Journal of Pharmacology and Experimental Therapeutics.

February 1, 2010. ArmaGen receives Notice of Allowance from USPTO on broad therapeutic antibody delivery patent. The U.S. Patent and Trademark Office has issued a formal Notice of Allowance for the lead patent in ArmaGen’s platform technology on the delivery across the human blood-brain barrier (BBB) of therapeutic antibodies. Should the BBB drug delivery problem be solved, therapeutic antibodies can be developed as new drugs for multiple brain diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, bovine spongiform encephalopathy, West Nile virus encephalitis, neuro-AIDS, brain injury, spinal cord injury, metastatic cancer of the brain, metastatic breast cancer of the brain, primary cancer of the brain, or multiple sclerosis. The patent entitled "Fusion Antibodies That Cross the Blood-Brain Barrier in Both Directions," discloses the composition of genetically engineered antibodies that are transported across the BBB via receptor-mediated transport, and bind and inactivate pathologic antigens within the brain. The patent will ultimately provide broad protection for ArmaGen’s portfolio of therapeutic antibodies that have been re-engineered as IgG fusion proteins with receptor-specific molecular Trojan horses that cross the BBB. Therapeutic antibodies, per se, are large molecule drugs that do not cross the BBB. However, following the re-engineering of the therapeutic antibody as an IgG fusion protein with ArmaGen's molecular Trojan horse, a new chemical entity is created that both crosses the BBB via receptor-mediated transport and retains high affinity binding of the therapeutic antibody for the target antigen in brain.

January 4, 2010. ArmaGen expands treatments for the brain in lysosomal enzyme disorders. ArmaGen has re-engineered the human lysosomal enzyme, iduronate 2-sulfatase (IDS), as an IgG fusion protein. The IDS is fused to a genetically engineered monoclonal antibody (MAb) against the human insulin receptor (HIR). The HIRMAb acts as a molecular Trojan horse to ferry the IDS across the human blood-brain barrier (BBB) for the treatment of the brain in the lysosomal storage disorder called Mucopolysaccharidosis (MPS) Type II, or Hunter's syndrome. Another lysosomal storage disorder that affects the brain is MPS Type I, Hurler's syndrome, which is caused by a deficiency of the lysosomal enzyme, iduronidase (IDUA). Patients with Hunter's or Hurler's syndromes have serious brain involvement, which is refractory to conventional enzyme replacement therapy, because the recombinant enzyme does not cross the BBB, and cannot penetrate the brain from blood. Following re-engineering of the lysosomal enzyme as a fusion protein with the BBB Trojan horse IgG, the enzyme penetrates the brain, and retains high lysosomal enzyme activity (Biotechnology & Bioengineering). The HIRMAb-IDUA fusion protein exhibited an excellent safety profile in a dose-ranging study in primates (Journal of Biotechnology). The most recent work describing the HIRMAb-IDS fusion protein for treatment of the brain in MPS Type II is published in Bioconjugate Chemistry.

2009

October 23, 2009. ArmaGen completes primate brain uptake study for AGT-160. ArmaGen has engineered AGT-160, a novel, dual-function IgG fusion protein capable of both receptor-mediated transport through the human blood-brain barrier (BBB) and disaggregation of the amyloid plaque of Alzheimer's disease (AD). AGT-160 is formed by fusion of a single chain Fv (ScFv) antibody against the Abeta peptide of AD to a genetically engineered monoclonal antibody (MAb) against the human insulin receptor (HIR). The HIRMAb is transported across the BBB on the endogenous BBB insulin receptor, and acts as a molecular Trojan horse to ferry the anti-Abeta ScFv across the BBB. The anti-Abeta monoclonal antibodies used in conventional passive immune therapy of AD do not cross the BBB in the absence of BBB disruption. In addition, AGT-160 is rapidly cleared from blood, whereas convential MAb's have prolonged blood residence times leading to sustained increases in plasma Abeta peptide concentrations. AGT-160 is a new generation of antibody-based therapies of the brain, which are specifically engineered to cross the human BBB via receptor-mediated transport. The work is published in Biotechnology and Bioengineering. In parallel, ArmaGen has engineered the mouse homologue of AGT-160, called AGT-m160, which is a fusion protein of the anti-Abeta ScFv and a chimeric MAb against the mouse transferrin receptor (mTfR). The HIRMAb is not active in the mouse, and the mTfRMAb is used as a surrogate Trojan horse for drug delivery across the mouse BBB. AGT-m160 will be used in drug testing in AD transgenic mice. The genetic engineering, expression, and in vivo brain uptake of AGT-m160 in the mouse has been recently described, and the work is published in Molecular Pharmaceutics.

September 18, 2009. ArmaGen completes primate safety study for AGT-181. ArmaGen has engineered AGT-181, a novel IgG-lysosomal enzyme fusion protein capable of receptor-mediated transport through the human blood-brain barrier (BBB). AGT-181 is formed by fusion of human alpha-L-iduronidase (IDUA) to a genetically engineeered monoclonal antibody (MAb) to the human insulin receptor (HIR), and the initial work was published in Biotechnology & Bioengineering. The HIRMAb acts as a molecular Trojan horse to ferry the fused IDUA across the human BBB for the treatment of the brain of patients with Mucopolysaccharidosis (MPS) Type I (Hurler's syndrome). The FDA has granted Orphan Drug Designation to ArmaGen for AGT-181 treatment of the brain in MPS-I. The fusion protein was manufactured by ArmaGen with methodology that can be replicated in a GMP laboratory, and the study drug was administered to 8 adult Rhesus monkeys in a dose-ranging study. The repeat dosing study showed no toxicity at any of the treatment doses up to 20 mg/kg IV given twice a week. A plasma pharmacokinetics study was performed and immunoreactive AGT-181 was measured with a sandwich 2-site immuno-assay. A second immuno-assay was used to measure the immune response to repeat dosing of the fusion protein, and this showed no significant immune response in primates. The work is published in the Journal of Biotechnology.

July 30, 2009. ArmaGen engineers IgG-decoy receptor fusion protein. ArmaGen has engineered a novel IgG-decoy receptor fusion protein capable of receptor-mediated transport through the human blood-brain barrier (BBB). The decoy receptor is the extracellular domain of the human tumor necrosis factor-alpha receptor (TNFR) type II, and the IgG is a genetically engineered monoclonal antibody (MAb) against the human insulin receptor (HIR). The HIRMAb part of the fusion protein acts as a molecular Trojan horse to ferry the TNFR decoy receptor across the BBB for neutralization of TNF-alpha action in the central nervous system. The IgG-TNFR fusion protein could have applications for the acute treatment of brain disorders, include ischemic stroke, brain trauma, and spinal cord trauma, and for the chronic treatment of brain disorders, including neurodegeneration and depression. Apart from the TNFR, other decoy receptors can be re-engineered for receptor-mediated transport across the human BBB with the molecular Trojan horse platform technology. The work is published in Molecular Pharmaceutics.

April 10, 2009. ArmaGen plans First in Human clinical trial. ArmaGen’s lead therapeutic is a genetically engineered fusion protein of a neurotrophin and an engineered monoclonal antibody. The antibody crosses the human blood-brain barrier (BBB) and acts as a molecular Trojan horse to carry into brain the attached neuroprotective neurotrophin. In preparation for filing of the IND in 2009, ArmaGen has completed Phase 0 GLP Toxicology and Safety Pharmacology in 56 Rhesus monkeys; no toxicity was observed at any dosage level, and the high dose established a no observable adverse effect level for human testing. The GLP safety pharmacology and toxicology is reported in the 2009 Pharmaceutical Research. ArmaGen has executed a collaboration agreement with a Contract Manufacturing Organization, and cGMP manufacturing of the IgG-neurotrophin fusion protein has begun. A First in Human Phase I clinical trial of the IgG-neurotrophin will begin following completion of the cGMP manufacturing. This clinical trial will test the safety and pharmacokinetics of the first IgG-neurotrophin fusion protein to enter human clinical trials.

2008

October 27, 2008. ArmaGen engineers paraoxonase fusion protein for organophosphates. ArmaGen Technologies describes the genetic engineering, expression, and validation of a fusion protein of paraoxonase (PON)-1 and a genetically engineered monoclonal antibody (MAb) to the human insulin receptor (HIR). The new fusion protein is a bi-functional protein, which both degrades organophosphates, due to the PON-1 part of the fusion protein, and crosses the human blood-brain barrier (BBB), due to the HIRMAb part of the fusion protein. PON-1 is the most potent human organophosphatase. Organophosphate agents cause morbidity and mortality secondary to action within the brain behind the BBB. Therefore, it is important to engineer new treatments of organophosphate intoxication that cross the human BBB, such as the HIRMAb-PON-1 fusion protein. PON-1 also restricts the development of atherosclerosis, and the new HIRMAb-PON-1 fusion protein could be developed as a new treatment for cerebral arteriosclerosis. The work is published in Molecular Pharmaceutics.

September 12, 2008. ArmaGen produces Trojan horse specific for mouse brain. ArmaGen has genetically engineered molecular Trojan horses for biopharmaceutical drug delivery across the human blood-brain barrier (BBB). However, the Trojan horses for humans cross-react only with Rhesus monkeys and are not active in rodents. A molecular Trojan horse specific for the mouse BBB is now available following the genetic engineering, expression, and validation of a chimeric monoclonal antibody against a specific receptor/transporter on the mouse BBB. The variable regions of the antibody are derived from a rat IgG, and are spliced onto constant region from mouse IgG, and the chimeric antibody is 85% mouse sequence. The availability of the genes encoding the new chimeric antibody now make possible the engineering of IgG fusion proteins for brain drug delivery in the mouse. These surrogate therapeutic products will accelerate drug development in humans. The work is published in Biotechnology & Bioengineering.

June 1, 2008. ArmaGen receives funding from U.S. Army.The U.S. Army has awarded ArmaGen funding to further develop AGT-185, a novel fusion protein with dual properties of (a) transport across the human blood-brain barrier and (b) rapid hydrolysis of organophosphate chemical nerve gas agents. AGT-185 is the first organophosphatase to be re-engineered for transport across the BBB, to enable penetration into the human brain. The lethal mechanism of action of chemical nerve gas agents occurs within the central nervous system (CNS). Therefore, it is crucial that new treatments for acute exposure to chemical nerve gas agents are enabled to cross the BBB and penetrate the human brain. This is made possible with the use of the molecular Trojan horse platform technology developed by ArmaGen Technologies.

March 14, 2008. ArmaGen receives Notice of Allowance from the U.S. Patent and Trademark Office. The U.S. Patent and Trademark Office has granted a Notice of Allowance on Delivery of Pharmaceutical Agents Via the Human Insulin Receptor. The patent claims cover the genetic engineering of a monoclonal antibody (MAb) against the human insulin receptor (HIR). The HIRMAb acts as a molecular Trojan horse to ferry drugs across the human blood-brain barrier (BBB). The HIRMAb BBB molecular Trojan horse, in conjunction with other platform technologies developed by the Company, can be used to deliver virtually any large molecule biopharmaceutical through the human BBB. The HIRMAb, and fusion protein technology, can deliver recombinant proteins, monoclonal antibodies, and therapeutic enzymes to the human brain from blood. The HIRMAb, and avidin biotin technology (U.S. Patent 6,287,792), can deliver siRNA across the human BBB. The HIRMAb, and Trojan horse liposome technology (U.S. Patent 6,372,250), can deliver non-viral plasmid DNA across the human BBB. The work is published in Biotechnology & Bioengineering.

January 15, 2008. ArmaGen receives Orphan Drug Designation from the FDA for AGT-181. The U.S. Food and Drug Administration has granted ArmaGen Technologies Orphan Drug Designation for AGT-181 for the treatment of Mucopolysaccharidosis (MPS) Type I. MPS Type I is caused by an inherited defect leading to the low production of a lysosomal enzyme in the brain. The enzyme deficiency causes severe degeneration of brain cells. Enzyme replacement therapy does not treat the brain, because the enzyme does not cross the blood-brain barrier (BBB). ArmaGen has re-engineered the missing lysosomal enzyme as a fusion protein that is bi-functional, and both has lysosomal enzyme activity and crosses the human BBB via receptor-mediated transport. ArmaGen's re-engineering of lysosomal enzymes to cross the human BBB is described in the February 1, 2008 issue of Biotechnology & Bioengineering. The development of AGT-181 is the first enzyme pharmaceutical that has been specifically engineered to cross the human BBB and treat the brain in lysosomal storage disorders.

2007

November 8, 2007. Intravenous RNAi of the brain with targeted siRNA.RNA interference (RNAi) enables the knock down of pathologic genes with short interfering RNA (siRNA) duplexes. The limiting factor in the translation of RNAi therapeutics from cultured cell systems to the in vivo state is the siRNA delivery system. Anionic siRNA molecules are generally formulated as a polyplex with a cationic molecule. ArmaGen Technologies has developed a new siRNA delivery system that does not use cationic formulations. In the December, 2007, issue of Pharmaceutical Research, Armagen Technologies achieves intravenous RNAi in intra-cranial brain cancer in vivo with the intravenous injection of targeted siRNA. The breakthrough combines RNAi technology with 2 delivery technologies: receptor-specific molecular Trojan horses and avidin-biotin technology. The mono-biotinylated siRNA is bound with very high affinity to a conjugate of streptavidin and a receptor-specific monoclonal antibody (MAb) that both crosses the blood-brain barrier (BBB) and the tumor cell membrane. Avidin, and streptavidin, bind biotinylated ligands with a dissociation half time of 3 months, and these complexes are highly stable in vivo. ArmaGen technologies has genetically engineered an avidin-MAb fusion protein, AGT-3 (see Products), for the in vivo delivery of siRNA in humans, as described in Bioconjugate Chemistry.

September 14, 2007. Neuroscene podcast on the blood-brain barrier and brain drug development. Neuroscene.com posts 20 minute podcast discussion on the role of the blood-brain barrier (BBB) in brain drug development. Discussion includes a review of the major role played by the BBB in limiting drug penetration to the brain: >98% of small molecule drugs do not cross the BBB, and ~100% of large molecule drugs do not cross the BBB. Since all Big Pharma and Big Biotech firms lack in-house BBB drug targeting technology, the majority of brain drug development programs--for small or large molecules-will be terminated. The problem is traced to a chronic under-development in infrastructure, as the number of scientist currently being trained in the BBB is minimal. No academic neuroscience program in the U.S. emphasizes BBB transport biology, much less BBB drug targeting technology. The podcast can be accessed in the Cognition section of Neuroscene.com under the date of Sept. 7, 2007, or at http://www.neuroscene.com/index.php?post_id=255049, and click the 'direct download' link.

August 23, 2007. ArmaGen Technologies completes Pre-IND meeting with FDA. ArmaGen Technologies today completes a Pre-IND meeting with the FDA for the treatment of acute ischemic stroke with intravenous AGT-120 administered within 5 hours of the brain attack. The meeting highlights included discussion of clinical trial design, GLP Pharmacology-Toxicology, and GMP manufacturing of AGT-120, a recombinant fusion protein. AGT-120 is a neuroprotective neurotrophin that was genetically engineered specifically to cross the human blood-brain barrier (BBB) following intravenous administration. The BBB is intact during the first 5 hours after a stroke, when neuroprotection and the rescue of dying brain cells is still possible. Therefore, neuroprotective drugs for stroke must be enabled to cross the BBB in order to be clinically effective in acute ischemic stroke.

July 12, 2007. ArmaGen engineers neurotrophin fusion protein for neural repair.ArmaGen Technologies describes the genetic engineering, expression, activity, and blood-brain barrier transport in the primate of a bi-functional fusion protein. The work is published in the August 15, 2007 issue of Biotechnology and Bioengineering. The work shows that ArmaGen's molecular Trojan horse can deliver across the human and primate blood-brain barrier (BBB) a neurotrophin that is one of the most potent inducers of neural repair. The fusion protein is a bi-functional molecule that both binds a human BBB receptor, to trigger transport into brain from blood, and binds a neuronal tyrosine kinase receptor, to trigger neuroprotection. The fusion protein binds the human BBB with high activity, and induces neuroprotection in human neural cells. The fusion protein crosses the Rhesus monkey BBB in vivo, and increases by many-fold the neurotrophin concentration in primate brain.

March 21, 2007. ArmaGen engineers therapeutic antibody for Alzheimer's disease. ArmaGen Technologies describes the genetic engineering, expression, activity, and transport in the primate of a tri-functional fusion antibody therapeutic for Alzheimer's disease (AD). The work is published today in Bioconjugate Chemistry by the American Chemical Society (http://pubs.acs.org/journals/bcches/index.html). The work shows that ArmaGen's molecular Trojan horse can deliver across the human and primate blood-brain barrier (BBB) a monoclonal antibody therapeutic that binds and disaggregates the Abeta amyloid of AD. This is the first anti-Abeta antibody that has been specifically engineered to cross the BBB in both directions: from blood-to-brain, and brain-to-blood. Therapeutic antibodies for AD in the blood must have a mechanism to access the Abeta amyloid plaque in brain behind the BBB. Moreover, once in brain, there must be a mechanism for the Abeta/antibody complex to exit the brain and return to blood for final degradation in liver and spleen. These functions are all incorporated in this new tri-functional fusion antibody therapeutic for AD. A single injection of the antibody fusion protein in the brains of AD transgenic mice caused a nearly 40% reduction in the brain amyloid burden within 48 hours. The fusion antibody was rapidly transported in the blood to brain direction via the BBB insulin receptor and was rapidly transported in the brain to blood direction via the BBB Fc receptor.

2006

September 19, 2006. ArmaGen expands exclusive patent estate licensed from the University of California. ArmaGen Technologies and the University of California (UC) amend the Exclusive Patent License granted by the UC to ArmaGen to include new technology for the blood-brain barrier (BBB) delivery of a wide range of pharmaceuticals. The expanded license now includes the delivery of certain neurotrophins across the BBB for the treatment of stroke, and the delivery of lysosomal enzymes across the BBB for the treatment of lysosomal storage disorders. The amended license also includes the exclusive use of avidin-biotin technology in drug delivery.

September 18 , 2006. ArmaGen develops AGT-185 for the treatment of nerve gas exposure. ArmaGen Technologies initiates a new program on the development of AGT-185, a treatment for acute nerve gas exposure of the central nervous system (CNS). AGT-185 is a genetically engineered recombinant fusion protein, which is comprised of 2 parts: (a) a human enzyme that is the most potent agent causing degradation of chemical nerve gas agents, and (b) a molecular Trojan horse. The latter is able to cross the blood-brain barrier (BBB) and deliver the nerve gas degrading enzyme into the CNS. Nerve gas agents cause death by the action of these agents within the CNS behind the BBB. Therefore, it is crucial that nerve gas antidotes are engineered to cross the human BBB to degrade the chemical nerve gas molecules within the CNS.

June 26, 2006. ArmaGen develops AGT-140, a neurotrophin neuroprotective therapy for stroke. ArmaGen Technologies begins development of AGT-140, a novel recombinant neurotrophin fusion protein that is able to both cross the blood-brain barrier (BBB) and to induce neuroprotection in acute stroke. ArmaGen will develop AGT-120 (see above) and AGT-140 in parallel for the acute treatment and neuroprotection in stroke. The pharmacological effect of the 2 drugs in stroke will be additive, as AGT-120 and AGT-140 cause neuroprotection in different regions of the brain via different neurotrophin receptors. The drug development of AGT-140, in parallel with AGT-120, is designed to enable combination therapy for neuroprotection in stroke.

February 6, 2006. ArmaGen develops AGT-180, a lysosomal enzyme replacement therapy of the brain. ArmaGen Technologies initiates a program in Lysosomal Enzyme Replacement Therapy of the Brain. The work will produce a new genetically engineered form of a lysosomal enzyme that is enabled to cross the blood-brain barrier (BBB) following intravenous administration. With this new form of therapy, a lysosomal enzyme may be delivered to virtually all cells in the brain following an intravenous infusion, because the enzyme is delivered across the vascular wall of the brain, which forms the BBB. The lysosomal enzyme is fused to ArmaGen's molecular Trojan horse, which ferries the lysosomal enzyme from blood into the brain.

2005

September 28, 2005. ArmaGen receives Notice of Allowance on U.S. Patent, "Non-invasive gene targeting to ocular cells." ArmaGen Technologies receives Notice of Allowance on U.S. Patent, "Non-Invasive Gene Targeting to Ocular Cells." This technology uses Trojan Horse Liposomes to deliver non-viral gene therapies to the retina and other structures of the eye in humans. The gene therapy is administered by a simple intravenous injection and without viruses. The exogenous gene is distributed and expressed in the entire retina.

February 17, 2005. ArmaGen publishes pre-clinical validation of lysosomal enzyme delivery to the brain . ArmaGen Technologies pre-clinical validation of lysosomal enzyme delivery to brain is published today in the Fast Forward section of the Journal of Pharmacology and Experimental Therapeutics (http://jpet.aspetjournals.org/). The work shows that ArmaGen's molecular Trojan horse can deliver a 116,000 Dalton enzyme across the blood-brain barrier (BBB) of adult mice following an intravenous administration. Without the molecular Trojan horse, there is no brain uptake of the blood-borne enzyme, because the protein does not cross the BBB. Following enzyme attachment to the molecular Trojan horse, which carries the enzyme into brain via endogenous peptide receptor transporters within the BBB, the brain enzyme activity is increased 1000% above basal levels. The study provides the basis for future lysosomal enzyme therapy of the brain using genetically engineered fusion proteins of lysosomal enzymes and BBB molecular Trojan horses.

2004

September 30, 2004. ArmaGen gene delivery technology reviewed in Nature. Nature magazine reviews non-viral gene delivery technology developed by ArmaGen Technologies, Inc., in the Express Delivery box of the article entitled RNA Interference: the Silent Treatment.

April 27, 2004. ArmaGen brain delivery technology highlighted in Wall Street Journal. New Treatments for Brain Cancer article in Wall Street Journal highlights brain drug and gene delivey technology developed by ArmaGen Technologies, Inc.

April 2, 2004. ArmaGen signs exclusive patent agreement for technology platform with the University of California. ArmaGen Technologies signs Exclusive Patent and Bailment Agreement for 'Mediated Delivery Systems' with the University of California. The agreement gives ArmaGen exclusive, world-wide license rights to pending and world-wide issued patents comprising a broad patent estate covering multiple technology platforms for the delivery to brain, and other organs, of drugs, recombinant proteins, and non-viral gene medicines. Some areas covered by the exclusive license include:

technology platform for the use of molecular Trojan horses to ferry drugs across the blood-brain barrier
technology platform for the delivery of non-viral gene therapies to brain, as well as non-brain organs
delivery of non-viral gene therapies to the retina and other structures of the eye
genetically engineered molecular Trojan horse for drug and gene delivery across the human blood-brain barrier
antisense gene therapy for human brain cancer

March 18, 2004. ArmaGen develops AGT-2000, a non-viral gene therapy of brain cancer. ArmaGen Technologies announces program to develop AGT-2000, a non-viral gene therapy for primary and metastatic brain cancer. AGT-2000 is a new form of gene therapy for brain cancer that is active following an intravenous administration without viruses. The gene therapy knocks down an oncogenic gene common to both primary and metastatic brain cancer. The gene is delivered across the blood-brain barrier of brain cancer with the same molecular Trojan horses which are used to deliver ArmaGen's protein based therapeutics. Since the gene target is expressed in both primary and metastatic cancer of the brain, the potential market for AGT-2000 is > 100,000 cases per year in the U.S.

March 11, 2004. Company incorporated as ArmaGen Technologies, Inc. Company changes its name and status from Neurogene Technologies LLC to ArmaGen Technologies, Inc., a Delaware corporation.

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