IBT Presents Pan-Ebola and Pan-Filovirus Monoclonal Antibodies

Integrated BioTherapeutics, Inc. (IBT), a leader in infectious disease and filovirus research, today announced the discovery of novel Pan-Ebola and Pan-Filovirus monoclonal antibodies (mAbs). IBT scientists presented the new mAbs at the 7th International Symposium on Filoviruses held in Washington, DC.

IBT’s broad-spectrum filovirus mAbs and cocktails are planned for development as therapeutics against filoviruses Ebola (EBOV), Sudan (SUDV), Bundibugyo (BUDV), Reston (RESTV), and Marburg (MARV). Filoviruses are highly pathogenic, high-priority public health threats with no approved vaccines or therapeutics. Current monoclonal antibody and vaccine candidates are mostly strain-specific and primarily target EBOV Zaire. Filoviruses are endemic in Africa and have caused periodic outbreaks, including the ongoing international EBOV epidemic, and are also potential bioweapon and bioterrorist threats. Patients develop severe hemorrhagic disease with up to 90% mortality. There is thus a strong unmet public health and biodefense need for broad-spectrum treatments for these highly pathogenic viruses.

The broad-spectrum filovirus mAb candidates were discovered by immunizing mice and Rhesus macaques with IBT’s proprietary filovirus antigens, isolating and cloning B cells from the animals, screening mAbs for binding to filoviruses, and conducting affinity maturation. Development then proceeded to expressing test mAb lots as humanized chimeric monoclonal IgGs, followed by characterization and efficacy testing in mouse models.

Our novel mAb candidates and cocktails have shown intriguing protection in mice against a broad spectrum of filoviruses. Cocktails of these mAbs have shown complete protection against multiple filoviruses. Our broad-spectrum filovirus mAbs bind to novel pan-Ebola and pan-filovirus epitopes. The epitopes are conserved across multiple filoviruses, enabling broad-spectrum activity and suggesting emergence of viral resistance may be limited.

The antibodies could be deployed against filoviruses in the same way that monoclonal antibody treatment or collected serum from survivors have been used in the ongoing Ebola outbreak originating in West Africa. Our mAbs or cocktails could also be considered as a prophylactic in endemic areas, before travelling, or for caregivers in close contact with filovirus patients.

Our mAbs are at the lead selection stage. The next steps in development are to select one or more broad-spectrum mAbs or cocktails as preferred lead candidates, complete proof of concept studies in rodents and NHPs, and commence a program directed towards IND and Phase 1 clinical trials.

IBT's broad-spectrum filovirus mAbs have the following key advantages:

  • Potential for mAb or mAb cocktail to treat multiple filovirus diseases
  • Novel target epitopes conserved across multiple filoviruses enable broad-spectrum activity and suggest emergence of viral resistance may be limited
  • Ready for lead selection

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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