The HIV/AIDS Pandemic: Advances Made and Challenges Ahead David D. Ho, M.D. Aaron Diamond AIDS Research Center, The Rockefeller University Los Angeles, 1981: tip of the iceberg – acquired immunodeficiency syndrome (AIDS) Common characteristics: gay men with marked depletion of CD4 T cells CDC: Groups at risk for AIDS • • • • • • Homosexual men Sex Female sex partners Injection drug users Blood Blood transfusion recipients Hemophiliacs treated with factor VIII Mother to child Children born to infected women 1983: detection of the causative agent – human immunodeficiency virus (HIV) F. Barre-Sinoussi & L. Montagnier The Global HIV Pandemic: 25 million dead and 35 million living The epidemic rages on with 2.5 million new infections per year Leading causes of death in Africa, 2000 25.0 22.6 20.0 % of Total 15.0 10.1 9.1 10.0 6.7 5.5 4.3 5.0 3.6 3.1 2.9 2.3 0.0 HIV/AIDS Malaria Lower respiratory infections Perinatal conditions Diarrheal disease Measles TB Ischemic heart disease Cerebrovascular disease Maternal conditions HIV prevalence among pregnant women in South Africa, 1990 to 2001 HIV prevalence (%) 30 25 20 15 10 5 0 ‘90 ‘91 ‘92 ‘93 ‘94 ‘95 ‘96 ‘97 ‘98 ‘99 ‘00 ‘01 Orphans in Sub-Saharan Africa: >12 million HIV-1: the causative agent of AIDS HIV-1 genomic organization HIV-1 life cycle and cellular factors that facilitate or restrict virus replication Tetherin (Vpu) CD4, CCR5, CXCR4 Tsg101, ALIX, ESCRT TRIM5α Why? APOBEC3G (Vif) P-TEFb LEDGF HIV-1 life cycle and antiretroviral drugs entry inhibitors protease inhibitors RT inhibitors Integrase inhibitors 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 Sustained reduction of viral load by combination antiviral therapy 850,000 New AIDS cases 450,000 750,000 Death People living With AIDS 350,000 650,000 300,000 550,000 250,000 450,000 200,000 350,000 150,000 250,000 100,000 150,000 50,000 5,000 0 0 1986 1988 1990 1992 1994 1996 1998 2000 2002 Year No. of persons living with AIDS No. of cases and no. of deaths Decline in AIDS mortality in the U.S. with the use of combination antiretroviral therapy since 1995 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 Where are we in HIV vaccine development? • No protective vaccine available • No protective vaccine in the foreseeable future 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 Features of gp120 that preclude the efficient neutralization of HIV by antibodies Variable loops Glycosylation Entropic forces Chen et al. Nature, 433: 834, 2005. 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) 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. 21 PrEP with tenofovir +/- emtricitabine has gained traction 22 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 Ideal PrEP agent -Infrequently administered -No side effects -No overlap with current therapies 23 Ibalizumab: HIV-neutralizing mAb directed to domain 2 of human CD4 (5A8, TNX-355) Structure of ibalizumab Fab bound to 2-domain CD4 (2.2Å) Freeman et al, Structure, in press Contact sites between ibalizumab and CD4 Superimposition of known structures of ibalizumab Fab, CD4, and gp120 core 100 10 80 1 60 40 0.1 20 0.01 0 20 40 60 Viruses 80 100 IC5 0 ( g/mL) M aximum percent inhibition (M PI) Breadth and potency of ibalizumab (MPI and IC50) against a panel of 118 HIV clones Ibalizumab is active and safe in vivo in humans Gates Foundation support to explore its use for PrEP Phase 1a 1b 2a 2b N 30 22 82 113 Dose 10 mg/kg singledose, monotherapy 10 mg/kg weekly, 9 WK monotherapy 10 mg/kg, bi-weekly + OBR 800 mg Q2W vs. 2000 mg Q4W, +OBR Route IV IV IV IV Subjects HIV-positive adults on stable therapy HIV-positive adults on failing regimens HIV-positive adults w/multi-drug resistant HIV HIV-positive adults w/multi-drug resistant HIV CD4 D (cells/uL) +131 +112 +48 +49 VL D (log) -1.33 -0.95 -1.00 -1.96 Serious Events No drug-related SAEs No drug-related SAEs No drug-related SAEs No drug-related SAEs to date Superimposition of known structures of ibalizumab Fab, CD4, MHC II-TCR, Ibalizumab as PrEP 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 31 Ibalizumab PK in monkeys: SC versus IV 32 Making a better ibalizumab “Affinity maturation” Change IgG4 to IgG1-LALA Modify Fc to bind FcRn better Sustained release formulation Improving the stability of ibalizumab 34 “In vitro affinity maturation” to select higher affinity variants 35 Higher affinity variants of ibalizumab selected from CDR1H mutants 36 Improving ibalizumab breadth by attacking a second site m36 PG9, VRC01 A fusion construct attacking CD4 and gp120 simultaneously iMab-m36 m36 Figure 2. iMabm36 is active against ibalizumab-sensitive Fusion with viruses m36 broadens the breadth of ibalizumab and resistant iMab-S viruses iMab-R viruses 39 iMab-m36 is active against ibalizumab-resistant viruses iMab [1.6g/ml] iMab-m36 Viruses [1.6g/ml] G02 G02 m366 iMAb gel con G07 G07 G08 100 G09 G09 75 G10 50 G08 100 G10 50 G11 G11 25 G12 G12 10 - 4 10 - 3 10 - 2 10 - 1 10 1 -50 10 - 4 10 - 3 G18 10 - 2 G20 10 - 1 -25 -50 10 1 G18 G20 G21 G21 G22 G22 G25 G25 Other fusion constructs attacking both CD4 and gp120 PG9-scFv or VRC01-scFv PG9-iMab or VRC01-iMab VRC01 fusion also increases the breadth of ibalizumab iMab-VRC01 G02 G02 100 G08 100 G08 80 80 G09 G09 60 G11 G11 Neutralization (%) Neutralization (%) iMAb gelIIIcon iMab 60 40 20 0 -20 -40 0.0001 0.001 0.01 0.1 1 concentration (ug/mL) 10 40 G12 G12 G18 0 G18 G20 -20 G20 -40 G21 G21 20 0.0001 G22 G25 0.001 0.01 0.1 1 concentration (ug/mL) 10 G22 G25 Our ultimate goal 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.