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• Female sex partners• Injection drug users• Blood transfusion recipients• Hemophiliacs treated with factor VIII• Children born to infected women

Sex

Blood

Mother to child

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

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

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

(%)

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

TRIM5α

Tetherin

APOBEC3G

CD4, CCR5, CXCR4

LEDGF

P-TEFb

Tsg101, ALIX, ESCRT

(Vif)

(Vpu)

Why?

HIV-1 life cycle and antiretroviral drugs

RT inhibitors

protease inhibitors

entry 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

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

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

Chen et al. Nature, 433: 834, 2005.

Variable loops

Glycosylation

Entropic forces

Features of gp120 that preclude the efficient neutralization of HIV by antibodies

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)

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.

22

PrEP with tenofovir +/- emtricitabine has gained traction

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

Ibalizumab: HIV-neutralizing mAb directed to domain 2 of human CD4

(5A8, TNX-355)

Freeman et al, Structure, in press

Structure of ibalizumab Fab bound to 2-domain CD4 (2.2Å)

Contact sites between ibalizumab and CD4

Superimposition of known structures of ibalizumab Fab, CD4, and gp120 core

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

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

Superimposition of known structures of ibalizumab Fab, CD4, MHC II-TCR,

31

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

32

Ibalizumab PK in monkeys: SC versus IV

Making a better ibalizumab

“Affinity maturation”

Change IgG4 to IgG1-LALA

Modify Fc to bind FcRn better

Sustained release formulation

34

Improving the stability of ibalizumab

35

“In vitro affinity maturation” to select higher affinity variants

36

Higher affinity variants of ibalizumab selectedfrom CDR1H mutants

Improving ibalizumab breadth by attacking a second site

m36

PG9, VRC01

A fusion construct attacking CD4 and gp120 simultaneously

iMab-m36

m36

39

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

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

Other fusion constructs attacking both CD4 and gp120

PG9-scFv

PG9-iMab

or VRC01-scFv

or VRC01-iMab

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

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