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No conflicting financial interest to declare

No conflicting financial interest to declare. Navid Madani Dana -Farber Cancer Institute Harvard Medical School. A CD4-mimetic compound enhances vaccine efficacy against stringent immunodeficiency virus challenge. Globally 5,000 new infections per day. Nov 2017, UNAIDS.

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No conflicting financial interest to declare

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  1. No conflicting financial interest to declare

  2. Navid Madani Dana-Farber Cancer Institute Harvard Medical School A CD4-mimetic compound enhances vaccine efficacy against stringent immunodeficiency virus challenge

  3. Globally 5,000 new infections per day. Nov 2017, UNAIDS

  4. Global New HIV Infections Among Adults by Age and Sex UNAIDS, 2015

  5. Small-molecule CD4-mimetic compounds Closed conformations Open conformations

  6. Small-molecule CD4-mimetic compounds Closed conformations Open conformations

  7. Can a CD4-mimetic compound directly prevent infection resulting from a mucosal exposure to HIV-1?

  8. Protection of humanized BLT mice from vaginal HIV-1JR-CSF challenge

  9. Conclusions • CD4-mimetic compounds specifically and directly inhibit HIV-1 infection in tissue culture and in BLT-mouse.

  10. Small-molecule CD4-mimetic compounds Closed conformations Open conformations

  11. Do monkeys immunized with Envimmunogens raise antibodies that neutralize primary HIV-1 sensitized by a CD4-mimetic compound?

  12. Study design Immunogen Additive to challenge virus Group 1Human serum albumin BNM-III-170 Group 2 CH505 gp120 DMSO Group 3 CH505 gp120 BNM-III-170

  13. SHIV-C5 Challenge Heterologous Clade C transmitted/founder virus Tier 2/3 neutralization sensitivity Three high-dose (~3.5 AID50) intrarectal challenges!

  14. Protection of immunized NHP in the presence and the absence of a CD4-mimetic compound

  15. Duration of protective immunity

  16. Conclusions • A CD4-mimetic compound sensitizes primary HIV-1 to neutralization and ADCC by readily elicited antibodies • BNM-III-170 and a gp120-induced antibody response synergize in protecting monkeys from repeated high-dose intrarectal challenges with a heterologous transmitted/founder Clade C SHIV

  17. Relevance to Vaccine-induced HIV-1 Prophylaxis • CD4-mimetic compounds are unique among potential pre-exposure prophylaxis modalities in that they specifically sensitize HIV-1 to a host antibody response • Sustained-release CD4-mimetic compounds should increase the efficacy of any HIV-1 Env vaccine that is not 100% protective and that elicits antibodies directed against more “open” conformations of Env

  18. Pod-IVR design human-sized pod-IVR delivery channels drug core drug core polymer coating polymer coating silicone backfill silicone backfill single delivery channel three delivery channels Pod-IVR Components • Polymer-coated drug cores, referred to as “pods”, • An un-medicated, torus-shaped elastomeric support to hold the pods, • One or more delivery channels through the elastomer ring structure provide the primary release rate control and link the pods to vaginal fluids. close-up of pod With three delivery channels

  19. In Vitro BNM-III-170 Release Is Linear • Single pod IVR segements • N = 4 • Low drug loading to conserve API during formulation development • Scale up under way to extend release period as API becomes available

  20. Acknowledgements University of Montreal Shilei Ding Jeremie Prevost Jonathan Richard Andres Finzi Duke University Todd Bradley David Easterhoff Kan Luo Larry Liao Tony Moody Barton Haynes Beth Israel Deaconess Linh Mach Sampa Santra Dana-Farber Cancer Institute Joseph Sodroski Amy Princiotto Connie Zhao University of Pennsylvania Bruno Melillo Sharon Kirk Amos Smith III Columbia University Wayne Hendrickson Oak Crest Institute of Science Marc Baum John Moss University of California Davis Chris Miller Linda Fritts Innovation Award

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