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Bi-specific Antibodies Targeting Disease Caused by Encephalitic Alphaviruses

Description:

TECHNOLOGY AREA(S): Chem Bio_defense, Bio Medical 

OBJECTIVE: The objective of this effort is to identify and develop bi-specific antibodies that demonstrate the capability to cross the blood brain barrier and neutralize encephalitic strains of Alphaviruses. 

DESCRIPTION: There are no approved medical countermeasures that are available for the treatment of encephalitic alphavirus infections of interest to the Department of Defense (DoD). Innovative technologies are sought to explore the bi-specific antibody platform as a potential therapeutic modality targeting Encephalitic alphavirus infections. Additional bi-specific platform technologies will also be considered. This topic is intended to solicit responses from small businesses to develop Medical Countermeasures (MCMs) for these specific viruses. This topic, as solicited, includes acceptance criteria for the definition of project success and is intended to increase the number of potential MCMs in the anti-Alphavirus pipeline. Currently, there is a capability gap for the effective treatment of viral induced encephalitis. It is widely acknowledged that viruses such as those represented in the Alphavirus family, e.g. Eastern, Western, and Venezuelan Equine Encephalitis viruses, pose significant risk to the warfighter. The Alphaviruses are recognized as potential biological warfare agents. There are no approved or licensed medical countermeasures against diseases caused by Alphaviruses. Currently, the only Medical Countermeasure is supportive care. Alphavirus infections can cause two distinct clinical presentations. In the mode of lesser concern, the infection can exhibit symptomology ranging from virtually asymptomatic to typical ‘flu-like’ symptoms. However, Alphavirus infections can also lead to encephalitis and it is this manifestation that is of grave concern, as viral encephalitis often leads to death, or at the very least, prolonged incapacitation. The specific approach of the study and the pathogenic targets are to be determined by the individual investigators. 

PHASE I: The Phase I proof-of-concept must demonstrate the offeror can produce a high binding (pM) bi-specific antibody. Successful Phase I proof-of-concept is defined as a demonstration that a bi-specific antibody directed at either Eastern, Western, or Venezuelan Equine Encephalitis virus has nanomolar binding capability. The offeror need not show efficacy against a challenge in vivo; just that the antibody can bind to alphavirus and an appropriate target for crossing the blood brain barrier (BBB). 

PHASE II: Building upon a successful Phase I proof-of-concept technology demonstration, Phase II requires demonstration of permeability of the blood brain barrier as well as neutralization of the virus. Demonstration of the antibody crossing the BBB can be performed in an artificial system. Additionally the bi-specific antibody must demonstrate post exposure efficacy in vivo. The offeror will need to use a well-defined animal model that mimics human encephalitic disease; however, the development of the animal model is outside the scope of this topic. The successful demonstration could be for one or more of the encephalitic Alphaviruses. A candidate is considered successful if there is a statistically significant increase in survival of animals. Delayed time to treat will be further evaluated in Phase III. Phase II tasks should include demonstration of BBB permeability, efficacy proof-of-concept, chemistry, manufacturing, and controls (CMC) considerations, pilot lot production proof-of-concept experiments that successfully demonstrate the feasibility to manufacture the MCM, and a preliminary stability study. Other considerations for Phase II work includes formulation (route of administration), tissue cross reactivity (TCR), and pharmacokinetics (PK) evaluation. PHASE III: With successful completion of Phase II, Phase III will focus on refinement and expansion of the concept. A successful Phase III effort will culminate in a product that is effective against one or more Alphaviruses, to include Eastern, Western, and Venezuelan Equine Encephalitis viruses. A “tri-valent” medical countermeasure would represent a distinct advantage, but is not an absolute requirement. A dosing regime in line with an FDA Phase I human safety trial will be determined, as will delayed time to treat. The technology will be evaluated in animal models using lethal doses of Eastern, Western, or Venezuelan Equine Encephalitis virus, separately. Time points for delayed time to treat should include 48, 72, 96 hrs post clinical signs of infection, with statistically significant target rescue rates of 80%, 50%, and 35%, respectively. After the successful completion of the Phase III activities, additional tasks required to make the product marketable will include a pre-investigational new drug (IND) meeting with the FDA, and IND filing. This would require completion of all necessary IND enabling toxicology, PK studies required and cGMP manufacturing to support Phase I safety trials in healthy human volunteers. 

PHASE III: PHASE III: With successful completion of Phase II, Phase III will focus on refinement and expansion of the concept. A successful Phase III effort will culminate in a product that is effective against one or more Alphaviruses, to include Eastern, Western, and Venezuelan Equine Encephalitis viruses. A “tri-valent” medical countermeasure would represent a distinct advantage, but is not an absolute requirement. A dosing regime in line with an FDA Phase I human safety trial will be determined, as will delayed time to treat. The technology will be evaluated in animal models using lethal doses of Eastern, Western, or Venezuelan Equine Encephalitis virus, separately. Time points for delayed time to treat should include 48, 72, 96 hrs post clinical signs of infection, with statistically significant target rescue rates of 80%, 50%, and 35%, respectively. After the successful completion of the Phase III activities, additional tasks required to make the product marketable will include a pre-investigational new drug (IND) meeting with the FDA, and IND filing. This would require completion of all necessary IND enabling toxicology, PK studies required and cGMP manufacturing to support Phase I safety trials in healthy human volunteers. PHASE III DUAL USE APPLICATIONS: Beyond DoD use, the product would most certainly have world-wide acceptance in the medical community for a treatment of encephalitis caused by Eastern, Western, or Venezuelan Equine Encephalitis virus infection. Moreover, the product would likely prove effective against treating infection of the aforementioned pathogens prior to the encephalitic stage. 

REFERENCES: 

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10:  Steele, K.E., Twenhafel, N. A. REVIEW PAPER: Pathology of Animal Models of Alphavirus Encephalitis, Vet. Pathol., September 2010 47: 790-805.

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15:  Stanimirovic, D.B., Bani-Yaghoub, M., Perkins M., and Haqqani, A.S. Blood-brain barrier models: in vitro to in vivo translation in preclinical development of CNS-targeting biotherapeutics. Expert Opin Drug Discov. 2015 Feb

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17:  Watts, R. J., & Dennis, M. S. (2013). Bispecific antibodies for delivery into the brain. Current opinion in chemical biology, 17(3), 393-399.

18:  Yu, Y. J., Atwal, J. K., Zhang, Y., Tong, R. K., Wildsmith, K. R., Tan, C., ... & Bumbaca, D. (2014). Therapeutic bispecific antibodies cross the blood-brain barrier in nonhuman primates. Science translational medicine, 6(261), 261ra154-261ra154.

KEYWORDS: Alphavirus, Blood Brain Barrier, BBB, Eastern Equine Encephalitis Virus, Encephalitis, Nanobody, Venezuelan Equine Encephalitis Virus, Western Equine Encephalitis Virus 

CONTACT(S): 

Jayanand Vasudevan 

(703) 704-3129 

Jayand.vasudevan.civ@mail.mil 

Dr. Anthony Macaluso 

(301) 619-2016 

Michael Johnson 

(703) 767-3378 

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