the hiv/aids pandemic: advances made and challenges ahead
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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). - PowerPoint PPT PresentationTRANSCRIPT
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The HIV/AIDS Pandemic: Advances Made and Challenges Ahead
David D. Ho, M.D.
Aaron Diamond AIDS Research Center,
The Rockefeller University
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Los Angeles, 1981: tip of the iceberg – acquired immunodeficiency syndrome (AIDS)
Common characteristics: gay men with marked depletion of CD4 T cells
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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
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1983: detection of the causative agent – human immunodeficiency virus (HIV)
F. Barre-Sinoussi & L. Montagnier
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The Global HIV Pandemic: 25 million dead and 35 million living
The epidemic rages on with 2.5 million new infections per year
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Leading causes of death in Africa, 2000
22.6
10.19.1
6.75.5
4.3 3.6 3.1 2.9 2.3
0.0
5.0
10.0
15.0
20.0
25.0
HIV/AIDS Malaria Perinatalconditions
TB Cerebro-vascular disease
Diarrheal disease
Lowerrespiratory infections
Measles Ischemic heart
disease
Maternalconditions
% ofTotal
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HIV prevalence among pregnant women in South Africa, 1990 to 2001
0
5
10
15
20
25
30
‘90 ‘00‘91 ‘92 ‘93 ‘94 ‘95 ‘96 ‘97 ‘98 ‘99 ‘01
HIV
pre
va
len
ce
(%)
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Orphans in Sub-Saharan Africa: >12 million
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HIV-1: the causative agent of AIDS
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HIV-1 genomic organization
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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?
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HIV-1 life cycle and antiretroviral drugs
RT inhibitors
protease inhibitors
entry inhibitors
Integrase inhibitors
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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
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Sustained reduction of viral load by combination antiviral therapy
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Decline in AIDS mortality in the U.S. with the useof 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
DeathPeople livingWith AIDS
No
. o
f ca
ses
and
no
. o
f d
eath
s
No
. o
f p
erso
ns
livi
ng
wit
h A
IDS
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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
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Where are we in HIV vaccine development?
• No protective vaccine available
• No protective vaccine in the foreseeable future
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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
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Chen et al. Nature, 433: 834, 2005.
Variable loops
Glycosylation
Entropic forces
Features of gp120 that preclude the efficient neutralization of HIV by antibodies
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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)
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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.
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PrEP with tenofovir +/- emtricitabine has gained traction
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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
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Ibalizumab: HIV-neutralizing mAb directed to domain 2 of human CD4
(5A8, TNX-355)
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Freeman et al, Structure, in press
Structure of ibalizumab Fab bound to 2-domain CD4 (2.2Å)
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Contact sites between ibalizumab and CD4
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Superimposition of known structures of ibalizumab Fab, CD4, and gp120 core
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20 40 60 80 1000
20
40
60
80
100
0.01
0.1
1
10
Viruses
Ma
xim
um
pe
rce
nt
inh
ibit
ion
(M
PI)
IC5
0 ( g
/mL
)
Breadth and potency of ibalizumab (MPI and IC50)against a panel of 118 HIV clones
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Ibalizumab is active and safe in vivo in humans
Phase 1a 1b 2a 2b
N 30 22 82 113
Dose10 mg/kg single-
dose, monotherapy10 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
SubjectsHIV-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 (cells/uL)
+131 +112 +48 +49
VL 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
Gates Foundation support to explore its use for PrEP
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Superimposition of known structures of ibalizumab Fab, CD4, MHC II-TCR,
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Moving toward proof of principle with the current form:Phase 1 study in healthy volunteersPassive protection against SIV challenge in macaques
Making a better ibalizumab:Improve routeImprove stabilityImprove affinityImprove PKImprove breadth
Ultimate goal:Decrease dose to <10 mgDecrease frequency to 2 monthsDecrease cost
Ibalizumab as PrEP
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Ibalizumab PK in monkeys: SC versus IV
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Making a better ibalizumab
“Affinity maturation”
Change IgG4 to IgG1-LALA
Modify Fc to bind FcRn better
Sustained release formulation
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Improving the stability of ibalizumab
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“In vitro affinity maturation” to select higher affinity variants
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Higher affinity variants of ibalizumab selectedfrom CDR1H mutants
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Improving ibalizumab breadth by attacking a second site
m36
PG9, VRC01
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A fusion construct attacking CD4 and gp120 simultaneously
iMab-m36
m36
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Figure 2. iMabm36 is active against ibalizumab-sensitive and resistant viruses
iMab-S viruses iMab-R viruses
Fusion with m36 broadens the breadth of ibalizumab
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iMab-m36 is active against ibalizumab-resistant viruses
iMAb gel con
10 - 4 10 - 3 10 - 2 10 - 1 101
-50
50
100
G02
G07
G08
G09
G10
G11
G12
G18
G20
G21
G22
G25
m366
10 - 4 10 - 3 10 - 2 10 - 1 101
-50
-25
25
50
75
100
G02
G07
G08
G09
G10
G11
G12
G18
G20
G21
G22
G25
iMab [1.6g/ml] iMab-m36 [1.6g/ml] Viruses
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Other fusion constructs attacking both CD4 and gp120
PG9-scFv
PG9-iMab
or VRC01-scFv
or VRC01-iMab
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iMAb gel con
0.0001 0.001 0.01 0.1 1 10
-40
-20
0
20
40
60
80
100
G02
G08
G09
G11
G12
G18
G20
G21
G22
G25
Ne
utr
ali
zati
on
(%
)
concentration (ug/mL)
iMab-VRC01
0.0001 0.001 0.01 0.1 1 10
-40
-20
0
20
40
60
80
100
G02
G08
G09
G11
G12
G18
G20
G21
G22
G25
Ne
utr
ali
zati
on
(%
)
concentration (ug/mL)
VRC01 fusion also increases the breadth of ibalizumab
IIIiMab
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To create improved variants of ibalizumab and otherHIV-neutralizing monoclonal antibodies that are potent, broad, and could be given in low doses SConce every 2 months.
It has not escaped us that such improved biologicscould also be used, especially in combination, to change the paradigm of HIV therapy from daily to monthly regimens.
Our ultimate goal