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Slide 1 - The HIV/AIDS Pandemic: Advances Made and Challenges Ahead David D. Ho, M.D. Aaron Diamond AIDS Research Center, The Rockefeller University
Slide 2 - Los Angeles, 1981: tip of the iceberg – acquired immunodeficiency syndrome (AIDS) Common characteristics: gay men with marked depletion of CD4 T cells
Slide 3 - CDC: Groups at risk for AIDS Homosexual men Female sex partners Injection drug users Blood transfusion recipients Hemophiliacs treated with factor VIII Children born to infected women Sex Blood Mother to child
Slide 4 - 1983: detection of the causative agent – human immunodeficiency virus (HIV) F. Barre-Sinoussi & L. Montagnier
Slide 5 - The Global HIV Pandemic: 25 million dead and 35 million living The epidemic rages on with 2.5 million new infections per year
Slide 6 - Leading causes of death in Africa, 2000
Slide 7 - HIV prevalence among pregnant women in South Africa, 1990 to 2001
Slide 8 - Orphans in Sub-Saharan Africa: >12 million
Slide 9 - HIV-1: the causative agent of AIDS
Slide 10 - HIV-1 genomic organization
Slide 11 - HIV-1 life cycle and cellular factors that facilitate or restrict virus replication TRIM5α Tetherin APOBEC3G CD4, CCR5, CXCR4 LEDGF P-TEFb Tsg101, ALIX, ESCRT (Vif) (Vpu) Why?
Slide 12 - HIV-1 life cycle and antiretroviral drugs RT inhibitors protease inhibitors entry inhibitors Integrase inhibitors
Slide 13 - HIV-1 replication dynamics Duration: 1 d Cell t1/2: 0.7 d Virus t1/2: 30 min Virus production: 1010 to 1012 Darwinian evolution fast forward: >107 mutants per day: treat hard Heightened (4-6-fold) turnover of CD4 T-cells: treat early
Slide 14 - Sustained reduction of viral load by combination antiviral therapy
Slide 15 - Decline in AIDS mortality in the U.S. with the use of combination antiretroviral therapy since 1995 1986 1988 1990 1992 1994 1996 1998 2000 2002 Year 0 50,000 150,000 200,000 300,000 350,000 100,000 250,000 450,000 5,000 150,000 750,000 650,000 550,000 350,000 450,000 250,000 850,000 0 New AIDS cases Death People living With AIDS No. of cases and no. of deaths No. of persons living with AIDS
Slide 16 - Social injustice: U.S. vs. Africa 1. The delivery of drugs and services to the developing world 2. The importance of prevention: education and vaccine
Slide 17 - Where are we in HIV vaccine development? No protective vaccine available No protective vaccine in the foreseeable future
Slide 18 - Difficulties in developing an HIV vaccine During the natural course of HIV infection, the virus is seldom (<1%) well controlled by the immune system Superinfection has been well documented HIV is extremely plastic and rapidly escapes from immune recognition HIV is relatively resistant to antibody neutralization
Slide 19 - Chen et al. Nature, 433: 834, 2005. Variable loops Glycosylation Entropic forces Features of gp120 that preclude the efficient neutralization of HIV by antibodies
Slide 20 - Notable HIV-neutralizing monoclonal antibodies b12: CD4-binding site on gp120 2G12: carbohydrate on gp120 2F5, 4E10: membrane-proximal region of gp41 PG9: conformational epitope on gp120 (Science, 2009) VRC01: CD4-binding site on gp120 (Science, 2010) PRO140: anti-CCR5 (anti-co-receptor) Ibalizumab: anti-CD4 (anti-receptor)
Slide 21 - 21 Pre-exposure prophylaxis (PrEP) with HIV-neutralizing monoclonal antibodies If we are unable to induce neutralizing antibodies in vivo, why not produce them ex vivo for passive administration? And turn a heretofore intractable basic discovery problem into a more tangible engineering challenge.
Slide 22 - 22 PrEP with tenofovir +/- emtricitabine has gained traction
Slide 23 - 23 Concerns about daily oral PrEP Adherence difficulty of a daily drug regimen in a healthy person Potential long-term side effects of the drug(s) Tenofovir +/- emtricitabine form the cornerstone of frontline ARV therapy -Infrequently administered -No side effects -No overlap with current therapies Ideal PrEP agent
Slide 24 - Ibalizumab: HIV-neutralizing mAb directed to domain 2 of human CD4 (5A8, TNX-355)
Slide 25 - Freeman et al, Structure, in press Structure of ibalizumab Fab bound to 2-domain CD4 (2.2Å)
Slide 26 - Contact sites between ibalizumab and CD4
Slide 27 - Superimposition of known structures of ibalizumab Fab, CD4, and gp120 core
Slide 28 - Breadth and potency of ibalizumab (MPI and IC50) against a panel of 118 HIV clones
Slide 29 - Ibalizumab is active and safe in vivo in humans Gates Foundation support to explore its use for PrEP
Slide 30 - Superimposition of known structures of ibalizumab Fab, CD4, MHC II-TCR,
Slide 31 - 31 Moving toward proof of principle with the current form: Phase 1 study in healthy volunteers Passive protection against SIV challenge in macaques Making a better ibalizumab: Improve route Improve stability Improve affinity Improve PK Improve breadth Ultimate goal: Decrease dose to <10 mg Decrease frequency to 2 months Decrease cost Ibalizumab as PrEP
Slide 32 - 32 Ibalizumab PK in monkeys: SC versus IV
Slide 33 - Making a better ibalizumab “Affinity maturation” Change IgG4 to IgG1-LALA Modify Fc to bind FcRn better Sustained release formulation
Slide 34 - 34 Improving the stability of ibalizumab
Slide 35 - 35 “In vitro affinity maturation” to select higher affinity variants
Slide 36 - 36 Higher affinity variants of ibalizumab selected from CDR1H mutants
Slide 37 - Improving ibalizumab breadth by attacking a second site m36 PG9, VRC01
Slide 38 - A fusion construct attacking CD4 and gp120 simultaneously
Slide 39 - 39 iMab-S viruses iMab-R viruses Fusion with m36 broadens the breadth of ibalizumab
Slide 40 - iMab-m36 is active against ibalizumab-resistant viruses
Slide 41 - Other fusion constructs attacking both CD4 and gp120 or VRC01-scFv or VRC01-iMab
Slide 42 - VRC01 fusion also increases the breadth of ibalizumab III iMab
Slide 43 - To create improved variants of ibalizumab and other HIV-neutralizing monoclonal antibodies that are potent, broad, and could be given in low doses SC once every 2 months. It has not escaped us that such improved biologics could also be used, especially in combination, to change the paradigm of HIV therapy from daily to monthly regimens. Our ultimate goal