International Society for Antiviral Research (ISAR) News Vol. 26 No.2

View the Article at: http://c.ymcdn.com/sites/www.isar-icar.com/resource/resmgr/docs/isar_news_avr_26_2.pdf

ISAR News – Newsletter for of the International Society for Antiviral Research. Hodge, V. Sampath, A. (2016) ISAR News 26(2).

Tell us about your career path

I am a molecular biologist with a deep interest in virology. I did my Ph.D. work at the University of Mainz, Germany on the mechanisms of action of type 1 interferons in hematopoietic cells. During this time, I developed a strong interest in cell signaling processes initiated by cytokines. During my postdoctoral fellowship at the University of Virginia I worked on signal transduction of IL2, IL4 and IL-13 and discovered the human IL-13 receptor. My interest in signaling led me to work on membrane microdomains that are often used by various cellular response mediators and also viruses such as HIV. In 2000, I joined the US Army Medical Research Institute of Infectious Diseases (USAMRIID) where I had a chance to use my knowledge of membrane microdomain to initiate a project on filoviruses. During this time, we worked out a method to generate Ebola virus-like particles (VLPs) and went on to demonstrate its utility as a vaccine for filoviruses. This work led to several high impact publications in J Exp Med, PNAS, and JID. In 2007 I ventured out of USAMRIID to start the biotechnology company Integrated BioTherapeutics (IBT). October 2016 ISAR News Vol. 26 No. 2 Antiviral Research 14

How did you start Integrated Biotherapeutics?

I started IBT in 2007 with a focus on emerging infectious diseases and biodefense and with the initial objective of transitioning some of the discoveries we had made at USAMRIID to actual products. Unlike most biotech companies I started IBT entirely based on government grants and contracts and with no private equity. Over the past 9 years we have been able to secure over $45M in government funding, and have also supplemented this capital with antiviral and anti-bacterial services that we offer to the pharmaceutical industry. The combination of product development and discovery services is a unique feature of our business model. In the meantime, the company has grown to 34 people, and now operates a state of the art laboratory and a vivarium for small animals. A primary focus of IBT is the development of broadly protective therapeutic antibodies against several viral targets including filoviruses, arenaviruses, and alphaviruses. Over the past few years we have developed strategies to drive broadly neutralizing antibody response in macaques using engineered filovirus glycoproteins and VLPs. In collaboration with Steven Foung’s lab at Stanford and Yuxing Li’s lab at University of Maryland, we succeeded to generate the first in class broadly neutralizing antibodies that are protective against multiple filoviruses. This is a critical milestone in the fight against filoviruses. During the 2014 Ebola virus disease (EVD) outbreak, we were lucky that at least some products against the Zaire strain were nearing the finish line. But other filovirus species like Sudan, Bundibugyo, and Marburg viruses have also caused sizable outbreaks. It is impossible to predict what species will hit the next time, so we should be prepared. Our broadly neutralizing antibodies offer a potential solution for this problem.

What aspect of your research have you found most satisfying?

Although I am operating a business, the most exciting part of my day to day work is looking at data and discussing it with our scientists. Being in the position to do research and yet see a direct link to real applications and the mesmerizing thought that what you make in your lab today may, some day, save a person’s life is a satisfaction no amount of money can buy. We are so grateful to funding agencies as the grant funding allows us to do our research without the pressure from investors whose timelines often don’t take the unpredictable nature of scientific research into account.

What are your thoughts on antibody-based therapeutics?

I know that ISAR is heavily focused on small molecule antivirals, and this is understandable. But we should remember that the immune system evolved in the first place to fight invading pathogens. Yet, in the 21st century of over 40 FDA approved monoclonal antibodies only two are for infectious diseases. I think this is primarily driven by the focus of the pharmaceutical industry on the lucrative market of cancer and inflammation, rather than an inherent difficulty of making effective antibody-based therapeutics for infectious diseases. Recent advancements in antibody manufacturing is driving down the cost of goods. Structural biology and advances in protein engineering are helping us design much smarter antibodies with higher specificity and affinity, as well as broader reactivity. Novel technologies are evolving to generate bispecific and tri-specific antibodies that could fundamentally change what can be achieved with antibody as a drug. We have seen better antibodies emerging for RSV, influenza, HIV, alphaviruses such as chikungunya, Zika, and filoviruses. This increased activity within this space driven by the urgency of the recent large outbreaks (Ebola, Zika, influenza), will hopefully result in major breakthroughs and growing number of FDA-approved antibody-based therapeutics for infectious diseases.

How has ISAR contributed in your career?

As a scientist whose research is focused on antiviral antibodies and the ISAR focus being on small molecule I am not a typical ISAR member. However, our company works extensively with pharmaceutical industry for testing antivirals, mostly small molecules in vitro and animal models. For our team the annual ISAR meeting is a unique opportunity to get updated on the newest developments in the field and new methodologies that could directly be applied in our service business. Maybe the best part of attending ISAR meetings is the opportunity to network with the best scientists in the field and access to important resources through these contacts. However, I would like to see ISAR pay more attention to antibodies and try to attract scientists working on antiviral antibody therapeutics to attend ISAR. Having scientists from both sides of the aisle with October 2016 ISAR News Vol. 26 No. 2 Antiviral Research 15 their unique perspectives will only enrich future ISAR meetings.

Publications

Immunization-Elicited Broadly Protective Antibody Reveals Ebolavirus Fusion Loop as a Site of Vulnerability.  Zhao X, Howell KA, He S, Brannan JM, Wec AZ, Davidson E, Turner HL, Chiang CI, Lei L, Fels JM, Vu H, Shulenin S, Turonis AN, Kuehne AI, Liu G, Ta M, Wang Y, Sundling C, Xiao Y, Spence JS, Doranz BJ, Holtsberg FW, Ward AB, Chandran K, Dye JM, Qiu X, Li Y, Aman MJ.  Cell. 2017 May 18;169(5):891-904.e15. doi: 10.1016/j.cell.2017.04.038.

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Cooperativity Enables Non-neutralizing Antibodies to Neutralize Ebolavirus.  Howell KA, Brannan JM, Bryan C, McNeal A, Davidson E, Turner HL, Vu H, Shulenin S, He S, Kuehne A, Herbert AS, Qiu X, Doranz BJ, Holtsberg FW, Ward AB, Dye JM, Aman MJ.  Cell Rep. 2017 Apr 11;19(2):413-424. doi: 10.1016/j.celrep.2017.03.049.

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Protective efficacy of a novel alpha hemolysin subunit vaccine (AT62) against Staphylococcus aureus skin and soft tissue infections.  Adhikari RP, Thompson CD, Aman MJ, Lee JC.  Vaccine. 2016 Dec 7;34(50):6402-6407. doi:10.1016/j.vaccine.2016.09.061. Epub 2016 Nov 12.
 

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Safety and Immunogenicity of a Parenterally Administered, Structure-Based Rationally Modified Recombinant Staphylococcal Enterotoxin B Protein Vaccine, STEBVax. Chen WH, Pasetti MF, Adhikari RP, Baughman H, Douglas R, El-Khorazaty J, Greenberg N, Holtsberg FW, Liao GC, Reymann MK, Wang X, Warfield KL, Aman MJ. Clin Vaccine Immunol. 2016 Dec 5;23(12):918-925. Print 2016 Dec.
 

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A "Trojan Horse" Bispecific Antibody Strategy for Broad Protection against Ebolaviruses. Wec, A.Z. Nyakatura, E.K. Herbert, A.S. Howell, K.A. Holtsberg, F.W. Bakken, R.R. Mittler, E. Christin, J.R. Shulenin, S. Jangra, R.K. Bharrhan, S. Kuehne, A.I. Bornholdt, Z.A. Flyak, A.I. Saphire, E. Crowe Jr., J.E. Aman, M.J. Dye, J.M. Lai, J.R. Chandran, K. (2016) Science 8(2016). doi: 10.1126/science.aag3267

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Feverish Quest for Ebola Immunotherapy: Straight or Cocktail?  Aman, M.J. Saphire, EO. (2016) Trends Microbiol 10(1016). pii: SD966-842X(16)30049-X

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Zika Virus: A New Animal Model for an Arbovirus.  Aman, M.J. Kashanchi, F. (2016) PLoS Negl Trop Dis 10(5): e0004702. doi:10.1371/journal.pntd.0004702

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Virus-Like Particle Vaccination Protects Nonhuman Primates from Lethal Aerosol Exposure with Marburgvirus (VLP Vaccination Protects Macaques against Aerosol Challenges).  Dye JM, Warfield KL, Wells JB, Unfer RC, Shulenin S, Vu H, Nichols DK, Aman MJ, Bavari S. Viruses. 2016 Apr 8;8(4). pii: E94. doi: 10.3390/v8040094

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Antibody Treatment of Ebola and Sudan Virus Infection via a Uniquely Exposed Epitope within the Glycoprotein Receptor-Binding Site.  Howell KA, Qiu X, Brannan JM, Bryan C, Davidson E, Holtsberg FW, Wec AZ, Shulenin S, Biggins JE, Douglas R, Enterlein SG, Turner HL, Pallesen J, Murin CD, He S, Kroeker K, Vu H, Herbert AS, Fusco ML, Nyakatura EK, Lai JR, Keck ZY, Foung SKH, Saphire EO, Zeitlin L, Ward AB, Chandran K, Doranz BJ, Kobinger GP, Dye JM, Aman MJ. (2016) Cell Reports 15, 1–13.

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Monoclonal antibody therapy for Junin virus infection.  Zeitlin L, Geisbert JB, Deer DJ, Fenton KA, Bohorov O, Bohorova N, Goodman C, Kim D, Hiatt A, Pauly MH, Velasco J, Whaley KJ, Altmann F, Gruber C, Steinkellner H, Honko AN, Kuehne AI, Aman MJ, Sahandi S, Enterlein S, Zhan X, Enria D, Geisbert TW. Proc Natl Acad Sci U S A. 2016 Apr 19;113(16):4458-63.

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Aman MJ, Chasing Ebola through the Endosomal Labyrinth:, MBio, 2016, 7(2):e00346-16

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Holtsberg et al., Pan-ebolavirus and Pan-filovirus Mouse Monoclonal Antibodies: Protection against Ebola and Sudan Viruses, J Virol, 2014

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Keck et al., Macaque Monoclonal Antibodies Targeting Novel Conserved Epitopes within Filovirus Glycoprotein, J Virol, 2014

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Adhikari et al., Antibodies to S. aureus LukS-PV Attenuated Subunit Vaccine Neutralize a Broad Spectrum of Canonical and Non-Canonical Bicomponent Leukotoxin Pairs, PLoS One, 2015

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Fusco et al., Protective mAbs and Cross-Reactive mAbs Raised by Immunization with Engineered Marburg Virus GPs, PLoS Pathog, 2015

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Warfield et al., Homologous and heterologous protection of nonhuman primates by Ebola and Sudan virus-like particles, PLoS One, 2015

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Sully et al., A tripartite cocktail of chimeric monoclonal antibodies passively protects mice against ricin, staphylococcal enterotoxin B and Clostridium perfringens epsilon toxin, Toxicon, 2014

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Warfield et al., Vaccinating captive chimpanzees to save wild chimpanzees, Proc Natl Acad Sci USA, 2014

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Aman and Adhikari, Staphylococcal bicomponent pore-forming toxins: targets for prophylaxis and immunotherapy, Toxins, 2014

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Karauzum et al., Structurally designed attenuated subunit vaccines for S. aureus LukS-PV and LukF-PV confer protection in a mouse bacteremia model, PLoS One, 2013

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Adhikari et al., Lower antibody levels to Staphylococcus aureus exotoxins are associated with sepsis in hospitalized adults with invasive S. aureus infections, J Infect Dis, 2012

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Adhikari et al., Novel structurally designed vaccine for S. aureus α-hemolysin: protection against bacteremia and pneumonia, PLoS One, 2012.

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