Orion BioScience Inc. has developed a "Soluble Antigen Array" (SAgA) therapeutic that displays multiple copies of aquaporin-4 epitope for targeted clearance of the auto reactive NMO-IgG antibody in patients with neuromyelitis optica (NMO). The product is intended to selectively clear NMO-IgG while limiting interaction with other non-NMO specific antibodies, thereby reducing side effects often seen with global immunosuppressants. Orion's SAgA technology displays multiple copies of AQP4 epitope along a flexible polymer backbone and will initiate endogenous reticuloendothelial clearance mechanisms through antibody agglomeration. Blindness is the primary clinical outcome of NMO induced attacks;however, severe attacks can also lead to extensive transverse myelitis and paralysis. The ten year mortality rate after initial diagnosis in patients with NMO is >25%, however, no dedicated NMO therapeutic is available. A majority of symptoms result from the binding of NMO-IgG to AQP4, followed by initiation of the complement cascade and eosinophil recruitment. Systemic corticosteroids such as prednisolone and methyl-prednisolone, and antibodies targeting B cells or complement clearance are the current course of treatment. However, the systemic toxicity and severe immunosuppression limit both the treatment window and dosing frequency. Previous results using the SAgA platform in the treatment of experimental autoimmune encephalomyelitis show that multivalent display of antigen and co-signal can alter the immune response and provide therapeutic benefit. Orion looks to further adapt this technology to provide a highly targeted (utilizing AQP4 epitopes specific to NMO-IgG binding) and highly potent (multivalent display increases binding avidity) to provide a superior therapeutic option to patients suffering from NMO. This SBIR grant focuses on two lines of investigation. The first is directed at establishing formulation and storage stability profiles of he synthesized SAgA materials. The second is evaluating binding specificity using SAgAs manufactured with individual and combinations of known AQP4 epitopes in NMO- positive and healthy patient sera. The proposed aims will position Orion to move forward into Phase II studies with one or more lead compounds for pre-clinical and IND enabling studies.

Public Health Relevance

Formation of lesions along the optic nerve and spinal column in patients with neuromyelitis optica (NMO) has been shown to be associated with the binding of the auto reactive antibody, NMO-IgG, to the aquaporin-4 (AQP4) water channel. If un- or inadequately treated, NMO disease progression leads to blindness, paralysis and a 10 year mortality rate of >25%. No dedicated drug therapies exist resulting in the off label use of global immunosuppressants or multiple sclerosis therapies, which provide minimal effectiveness, and in some cases cause disease exacerbation. Additionally, severe toxicological and immunological side effects limit the treatment duration. None of these options treat the root cause of auto reactive antibody binding to AQP4. To address the documented need for a dedicated NMO treatment option, Orion BioScience Inc. is developing Soluble Antigen Array (SAgA) therapies which specifically target NMO-IgG, facilitate antibody agglomeration, and promote removal from circulation via reticuloendothelial clearance mechanisms. This provides patients a real therapeutic option with decreased side effects for treatment of NMO.

National Institute of Health (NIH)
National Eye Institute (NEI)
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
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Special Emphasis Panel (ZRG1-ETTN-G (12))
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Wujek, Jerome R
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Orion Bioscience, Inc.
United States
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