Antibody-mediated therapy approaches in HIV-1 infection

60 Pages·2017·2.34 MB·English

Antibody-mediated therapy approaches in
HIV-1 infection
Florian Klein Arevir Meeting

Institute of Virology 4th of May 2018
University of Cologne Cologne
Structure and antiviral activity of human antibodies
Antigen (e.g. Virus)
V V
H H
V
V L
L
Fab
CH CH
C
C L
L
H
C C
H H
Fc
C C
H H
COOH COOH
Immune cells
(effector functions)
Structure and antiviral activity of human antibodies
Antigen (e.g. Virus)
V V
H H
V
V L
L
Fab
CH CH
C
C L
L
H
C C
H H
Fc
C C
H H
COOH COOH
Immune cells
(effector functions)
Structure and antiviral activity of human antibodies
Antigen (e.g. Virus)
• Target and neutralize broad
sprectrum of antigens
(Victora et al., Annu Rev Immunol. 2012)
V V
H
V H VL
L
Fab
CH CH • Effector mechanisms to
C
C L
L
clear infection (e.g. ADCC)
H
(Nimmerjahn et al., Nat Rev. Immunol 2007)
C C
H H
Fc
C C Control of infection
H H
(Burton, Nat. Rev. Immunol., 2002)
COOH COOH

Prevention of infection
(Plotkin, Clin. Vaccine Immunol. 2010)

Immune cells
(effector functions)
Isolation of potent broadly HIV-1 neutralizing antibodies
Elite Neutralizer (1%)
HIV-1
Isolation of potent broadly HIV-1 neutralizing antibodies
Elite Neutralizer (1%)
bNAb
HIV-1
Scheid et al., Science 2011, Walker et al., Science 2009, Wu et al., Science 2010, Corti et al., Plos One
2010, Diskin et al., Science 2011, Walker et al., Nature 2011, Mouquet et al., PNAS 2012, Klein et al., J
Exp Med 2012, Huang et al., Nature 2012, Bonsignori et al., J. Virol 2012
Isolation of potent broadly HIV-1 neutralizing antibodies
1994 - 2008

)
h
t
d
a
e
r
b
(

n
Elite Neutralizer (1%)
o
ti
a
z
ali
r
t
u
e
N
2017

)
h
bNAb dt
a
e
r
b
(

n
o
HIV-1 ti
a
z
ali
r
t
u
e
N
Neutralization (potency)
Highly potent broadly HIV-1 neutralizing antibodies
1994 - 2008

)
h
t
d
a
V1/V2 loop e
r
b
V3 loop (

n
o
ti
a
z
ali
CD4bs tr
u
e
N
2017
MPER
Interface )h
t
d
a
e
r
b
(

n
o
HIV-1 Envelope protein ati
z
ali
r
t
u
e
N
Neutralization (potency)
Highly potent broadly HIV-1 neutralizing antibodies
Antibody-mediated preventtion
V1/V2 loop
V3 loop
control bNAbs
CD4bs
)
ml
s/
e
pi
o
c
MPER (
Interface d
a
o
al l
r
Vi
Days post SHIV challenge Days post SHIV challenge
HIV-1 Envelope protein
Klein et al., Science, 2013 Moldt et al., PNAS 2012, Gautam et al., Nature 2016
Highly potent broadly HIV-1 neutralizing antibodies
Antibody-mediated preventtion
V1/V2 loop
V3 loop
control bNAbs
CD4bs
)
ml
s/
e
pi
o
c
MPER (
Interface d
a
o
al l
r
Vi
Days post SHIV challenge Days post SHIV challenge
HIV-1 Envelope protein
Clinical Trials

(VRC01, phase 2b, ongoing)

• HVTN 704/HPTN 8 5 (2700 subjects)
• HVTN 703/HPTN 0 81 (1500 subjects)
Klein et al., Science, 2013