Therapeutic HIV Vaccines and Broadly
Neutralizing Antibodies
Magdalena E. Sobieszczyk
Associate Professor of Medicine at CUMC
Columbia University Irving Medical Center
New York, New York
Slide 3 of 40
Learning Objectives
After attending this presentation, learners will be able to:
• Describe goals and challenges of therapeutic vaccine
development
• Describe the status of clinical development of broadly
neutralizing antibodies (bNAbs) for treatment
• Describe advances in bNAbs
Slide 4 of 40
Outline
• Why pursue ART-free approaches like therapeutic vaccines and
antibodies to HIV-1 treatment?
• What are therapeutic vaccines
• What are broadly neutralizing antibodies - bNAbs
• Advances in bNAbs for treatment and potential for cure
New York, New York, March 18, 2019
Page 1
Slide 5 of 40
Why Pursue ART-free Approaches to Treatment?
• Impossible to eradicate HIV from latent viral reservoirs
with ART alone
• Important to have OPTIONS including agents with
potential for less frequent dosing
• Gaps in ART delivery
• Long term side effects of ART
• Adherence and retention in care remain a challenge
Is it possible to achieve sustained HIV-1 remission/control
without antiretrovirals?
Slide 6 of 40
Rationale for Therapeutic HIV-1 Vaccines
• Evidence from individuals whose immune system naturally
control HIV-1 without ART (LTNP, elite controllers)
▫ effective host mediated anti-HIV immunity is possible
• Is it possible to augment the host immune response to
kill infected CD4 T cells and neutralize circulating
virions?
Pantaleo &Levy, Curr Opin HIV AIDS 2013
Stephenson Curr Opin HIV AIDS 2018
Slide 7 of 40
Goals of a Therapeutic Vaccine
• At minimum
▫ Make simplified ART regimens possible
▫ Allow for periodic Analytic Treatment Interruption [ATI]
• Optimally
▫ Eliminate need for ART either by eradicating the virus or
inducing host immune response capable of controlling virus
replication
In placebo-controlled studies that included interruption of ART to
measure efficacy, therapeutic vaccine not successful in achieving
durable suppression of HIV viremia.
New York, New York, March 18, 2019
Page 2
Slide 8 of 40
• No effect of DNA/rVSV therapeutic vaccination on control of HIV rebound
following ART interruption
• 26% of placebos sustained suppression of viremia after treatment
interruption
Slide 9 of 40
Selected Randomized Controlled Trials of Therapeutic Vaccines
Vaccine Name
Population
Latency
Reversal
Agent
Result
DC
-HIV: Dendritic cells loaded w/heat
inactivated autologous HIV
ATI
No
Significant/transient
decr in VL
during ATI,
incr T cell responses
ALVAC
-HIV, Lipo-6T, IL-2: Canarypox vector
(
Env, Gag, Pol, Nef),
lipopeptide vaccine (
Nef, Gag, Pol, IL-2)
ATI
No
Induced HIV
-specific CD4 and
CD8 T cell responses which
predicted virologic control during
ATI
HIVAX: mutated HIV strain expressing range
HIV proteins
ATI: no
placebo
No
Broad responses/Reduced VL
vs. pre
-ART
DNA/
rVSV
ATI in pts
who started
ART in early
infection
No
Vx did not prevent viral rebound;
26% placebos had sustained
suppression viremia after ATI
MVA
-B: clade B gp120, Gag, Pol, and Nef
ATI
Yes
Disulfiram
Safe & immunogenic; no sig
effect on VL rebound after ATI or
viral reservoir with or without
LRA
Garcia et al JID 2011, Levy et al. AIDS 2005; Levy et al AIDS 2006; Tung
et al Vaccine 2016; Sneller et al Sci Trans Med 2017; Mothe et al J
Antimicrob Chemother 2015
Slide 10 of 40
Towards a More Effective Therapeutic Vaccine:
Improved Combination Approaches
• Add
Borducchi et al, Nature 2016.
Ad26/
MVA alone
•
Induced broad cellular immune
responses
• No clinically significant decrease
in VL setpoint after ATI
1.75 log reduction in VL
2.5-fold delay of viral rebound
after ATI
New York, New York, March 18, 2019
Page 3
Slide 11 of 40
Therapeutic Vaccines: Take Home Points
• No randomized controlled trials of therapeutic vaccination that
induced long-term remission after analytical treatment interruption
• Need vaccines that induce broad host immune responses to
recognize diverse escape viral variants after viral rebound
• Therapeutic vaccine may need to be paired with potent latency
reversal agent (eg vorinostat) or immune modulators (TLR7
agonist) to induce long-lasting remission
Stephenson, Curr Opin HIV AIDS 2018
Graziani & Angel, JIAS, 2015
Seddiki & Levy, Curr Opin HIV AIDS 2018
Slide 12 of 40
ARS Question 1: Would any of your HIV-infected patients
be interested in bNAb based therapies as an alternative
to ART?
1. None, my patients are happy taking daily ART
2. Yes but less than 25%
3. Yes, between 26-50%
4. Yes, between 51-75%
5. Yes, more than 76%
Slide 13 of 40
Potential use of Abs for HIV-1 Treatment
• Block HIV replication by inhibiting viral
entry into cell (neutralizing activity)
• Capable of engaging the host immune
system
▫ Mediate killing of infected cells (ADCC)
• Potential to clear latently infected cells
and enhance immune responses
against HIV-1
▫ Potentially target latent viral reservoir
Fig. Adapted Carillo et al, Frontiers Immunology 2018
New York, New York, March 18, 2019
Page 4
Slide 15 of 40
Slide 16 of 40
What are Broadly Neutralizing Antibodies
against HIV-1
• Minority of HIV-1 infected individuals (5-10%) develop the ability to
neutralize various heterologous viruses from different subtypes within
2-3 years after infection
• Very broad and potent neutralizing antibodies have been isolated from
these individuals
• Bind to relatively conserved regions of Env
• Passive transfer of bNAbs investigated for treatment, eradication/cure,
prevention, and to guide preventive vaccine design
Walker et al. Science 2009; Doria-Rose etal, Nature 2014; Liao et al. Nature 2013;
Bonsignori et al. Cell 2016; Martin van Gils, AIDS Conference 2018
Slide 17 of 40
Broadly cross-neutralizing antibodies have NO impact
on HIV disease progression: CAPRISA 002 Cohort
Gray et al J of Virology 2011
Slide courtesy L. Morris
New York, New York, March 18, 2019
Page 5
Slide 18 of 40
Broadly Neutralizing Antibody Targets on the HIV-1
Envelope Trimer
Burton & Hangartner. Annual Reviews 2016
Slide Adapted from Marit van Gils, PhD
Attachment points of Abs
capable of neutralizing wide
range of HIV isolates
Slide 19 of 40
gp41 MPER:
10e8
V1V2 Glycan:
PGT141-45, PGDM1400, CAP256-VRC26
CD4 Binding Site:
VRC01, 3BNC117, VRC07-523
N332 Glycan Supersite:
PGT121, 10-1074
Examples of Broadly Neutralizing Abs in
Clinical Development
Trimer (gp120/41)
8ANC195, PGT151
Slide adapted from presentations the Subramaniam, Kwong, and Wilson groups.
Slide 20 of 40
Passive Infusion of Broadly Neutralizing Antibodies
Delays the Rebound of Plasma HIV Viremia Following
Interruption of ART
• 13 ART-treated participants with 3BNC117-sensitive viruses
• Analytical treatment interruption (ATI) and 2 - 4 infusions
• Infusions delayed viral rebound average of 8.4 weeks vs. historical controls
• Rebound virus with low diversity and resistance to 3BNC117 in most ppt
Scheid et al Nature 2016
New York, New York, March 18, 2019
Page 6
Slide 21 of 40
• Participants not screened for VRC01 sensitivity
• Treatment interruption and 3-8 infusions
• Median time to plasma viral rebound = 4 weeks & 5.6 weeks
• Historical control for time to plasma rebound = 11 to 28 days
• Viral rebound: Polyclonal and despite high Ab levels in most ppt
Bar, et al NEJM 2016
Slide 22 of 40
Cohen & Caskey CurrOpHIVAIDS 2018; Lynch et al SciTransMed 2015; Caskey et al Nature 2015; Scheid et al Nature 2016; Bar et al NEJM 2016; Caskey et al Nat Med 2017
Selected Clinical Trials involving
bNAbs in HIV-1 infected individuals
Antibody
Population
Target
Major Findings
VRC01
On ART and
viremic
CD4
-bs
•
VL Decr 1.1–1.8 log
10
after single infusion
•
ATI: viral strains not selected for VRC01 sensitivity
Median delay in viral rebound of 4 and 5.6 wks after
ART d/c
•
t
1/2
12 days in HIV+
3BNC117
On ART &
viremic
CD4
-bs
•
Average VL Decr of 1.48 log
10
after single dose
•
ATI: Viral strains screened for 3BNC117 sensitivity:
Average delay in viral rebound of up to 9.9 wks after
ART d/c & multiple doses
•
t
1/2
9.6 days in HIV+
10
-1074
On ART and
viremic
V3 loop
•
VL Decr 1.52 log
10
after single infusion
•
Emergence of resistant viral strains in few wks
(sensitive to non-V3 loop Ab)
•
t
1/2
12.8 days in HIV+
PGT121
CROI 2019
On ART and
viremic
V3 loop
•
High baseline VL: 1.7 log
10
drop with rebound
resistant virus (5/9 responders)
•
Low baseline VL: 2 pts suppressed >6 months
PGDM 1400
Viremic
V1/V2 loop
•
Ongoing. Will evaluate PDGM1400 +/- PGT121
Slide 23 of 40
Optimizing bNAbs for the Treatment of HIV Infection
• More potent antibodies
• Extend half-life of antibodies
• Combinations of antibodies
• Next generation of antibodies
New York, New York, March 18, 2019
Page 7
V R C 0 1
3 B N C 1 1 7
V R C
0 7 - 5
2 3
N 6
P G T 1
2 1
1 0
- 1 0 7 4
P G D
M 1 4 0 0
C A
P 2 5 6 V
2
1 0 E
8 V
4
0 1 8 / V
R C 0 1
0 . 0 0 0 0 1
0 . 0 0 0 1
0 . 0 0 1
0 . 0 1
0 . 1
1
1 0
1 0 0
I C 8 0 T i t e r (
g / m l )
41 1
4 62 0
5 4 34 0 2 73
2
% resistant
More potent
CD4BS Glycan-V3 V1V2 Glycan MPER Tri-sp
Potency & Breadth: In Vitro Neutralization Profiles
Multi-clade
virus panel
(n=208)
Thanks to VRC
Slide 24 of 40
Slide 25 of 40
Potency & Breadth
Gama & Koup Annual Rev Med 2018
More potent
Increasing Breadth
Slide 26 of 40
Antibody Modifications Extend Half-life: Intermittent Dosing
• LS mutation: Two amino acid
mutation in Fc region of the Ab
• Increased affinity for neonatal Fc
receptor (FcRn): extend plasma
half-lives
• Potential for less frequent
administration of mAb
• Increased Ab at mucosal surface
in animal studies
• Studies with LS versions are
ongoing
VRC01LS vs VRC01 serum
concentrations
Julie Ledgerwood et al. J Virol. 2014
Gaudinski et al, PLOSMedicine 2018
New York, New York, March 18, 2019
Page 8
Slide 27 of 40
Modifications of Fc region can also Increase Effector
Functions
• Fc modifications to increase antibody dependent cell-mediated
cytotoxicity (ADCC) or phagocytosis
▫ Potentially reduce or target the HIV reservoir
• CROI 2019: Engineered variant of PGT121 with enhanced effector
function (GS-9722)
▫ Enhanced killing of HIV infected CD4+ T-cells by NK cells
Thomsen et al. Abstract 356. CROI 2019
Slide 28 of 40
Potential of Combination bNAb Therapy for the
Durable Control of HIV
• In studies to date, rebound viruses did not demonstrate
increased resistance to other Ab that target different
envelope epitopes
• Combinations of two or more bNAbs are likely to lead to
more robust and sustained antiviral effects
▫ Increase overall breadth and potency
▫ Prevent emergence of resistance
Slide 29 of 40
Combining Abs to Improve Potency and Breadth
Rui Kong et al. J. Virol. 2015;89:2659-2671
Rui Kong et al. J. Virol. 2015;89:2659-2671
New York, New York, March 18, 2019
Page 9
Slide 30 of 40
Combination bNAbs and Treatment
Interruption
• Patients Virologically suppressed on ART >24 months
• Pre-screened for 3BNC117 and 10-1074 sensitivity
• 3 infusions of combination Abs during Treatment interruption (ATI)
• Median duration of suppression with Ab-sensitive virus: 21 weeks
• Median duration of suppression with Ab-resistant virus: 5 weeks
Mendoza et al Nature 2018
Slide 31 of 40
Combination bNAbs and Treatment
Interruption
• 2 participants maintained virologic suppression long after Ab levels waned
• 1 remains suppressed
• Important to explore if bNAbs can be a component of cure strategies
Mendoza et al Nature 2018
Slide 32 of 40
Combination bNAbs
• Combinations will be necessary to increase overall breadth and
potency and to prevent the emergence of resistance
• Number of bNAbs required may differ based on the indication
▫ In active viremia: combination of 3 or 4 current bNAbs may
be required to cover the swarm of viruses present
• Screening for bNAb sensitity pre-therapy to potentially
reduce number of bNAbs required for Rx and amplify
efficacy
▫ CROI 2019: Potential of PhenoSense HIV nAB Assay
Reeves et. Abstract 305. CROI 2019
New York, New York, March 18, 2019
Page 10
Slide 33 of 40
Next Generation bNAb: Bispecific and Trispecific
• Engineered Ab (single protein) that targets multiple independent
epitopes on virus
• Potentially lower likelihood of escape mutations compared to single Ab
or combination of 2-3 Ab
• Enhanced potency and breadth
Montefiori et al. Cell, 2016; Huang et al, Cell 2016; Asokan et al, J Virol, 2015; Xu et al. Science 2017
Slide 34 of 40
Bispecific Antibodies Concept
Two different antibody binding arms on one IgG
Bispecific T-cell engager: CD3 and HIV-1
VRC07
PGT121
VRC07
anti-CD3
Killer T-cell
Infected
CD4 cell
Broader, more potent, less viral escape
Mediate cell killing
Slide courtesy John Mascola
Slide 35 of 40
Example of Bispecific Ab: 10E8.4/iMab
Y. Huang et al. Cell 2016.
• One arm of IgG binds an epitope
in the membrane proximal external
region (MPER) of gp41
• The other arm binds either the
HIV-1 CD4, or, CCR5 co-receptor
molecule on T-helper cell
• Phase 1, first in human, clinical
study for treatment and prevention
is starting 2019
New York, New York, March 18, 2019
Page 11
Slide 36 of 40
Trispecific Ab
• Combines specificities of 3 Abs binding to
▫ CD4 binding site & V1V2 glycan site
▫ membrane-proximal external region
• New data from CROI 2019
▫ Potent Fc effector functions in animal studies: promising for
mediating ADCC and phagocytosis
▫ Potent suppression of viral replication in viremic SHIV infected
animals
• Phase 1 ascending dose study in HIV-infected infected starting
2019Q1
Ling Xu et al, Science 2017
Pegu A et al, Abstract 28, CROI 2019
Slide 37 of 40
Desirable Properties of bNAbs
• Every 6 month regimen of passive transfer of combination
of bNAbs
• SC injection
▫ easier to implement
• Replaces daily antiretroviral therapy
• Safe & well tolerated
• Scalable [Inexpensive]
• Manufacturing: public private partnerships
Slide 38 of 40
Broadly Neutralizing Antibodies: Next Steps
• A new generation of highly potent and broadly neutralizing HIV-1
antibodies has been identified
• HIV-1 exhibits genetic diversity and viral escape mechanisms.
▫ Prudent to consider using a combination approach
▫ Potential to screen for bNAb sensitity prior to therapy?
• Like ART, combinations of mAbs could reduce the likelihood of
viral escape, and increase neutralization breadth
• Alternative delivery systems: gene delivery viral vectors Vector-
based antibody production in vivo
New York, New York, March 18, 2019
Page 12
Slide 39 of 40
Summary
• bNAbs are a promising approach towards durable control of HIV
rebound in absence of ART
▫ also actively pursued for prevention both as passive prevention
and platform for design of vaccines
• No randomized controlled trials of therapeutic vaccination that
induced long-term remission after analytical treatment interruption
• Combination strategies of bNAbs, therapeutic vaccines,
immunomodulators (e.g. TLR7 agonist) may be needed to diminish
the reservoir
Slide 40 of 40
Acknowledgements
• Scott Hammer
• John Mascola
• Larry Corey
• Shelly Karuna
• Lynn Morris
• David Montefiore
Question-and-Answer
Slide 40 of 40
New York, New York, March 18, 2019
Page 13