Dale and Betty Bumpers

Vaccine Research Center National Institute of Allergy and Infectious Diseases National Institutes of Health

IAS Satellite July19, 2015

Antibodies for Prevention and Treatment of HIV-1 Infection

John R. Mascola, M.D. Vaccine Research Center NIAID, NIH

Talk Outline  Background on HIV-1 neutralizing antibodies  Antibodies to prevent HIV-1 infection

 Potential role in treatment of infection Disclosure: VRC01 was isolated in my laboratory at VRC, NIAID, NIH. I am listed as inventor on an NIH patent for VRC01

HIV Env Trimer Structure (2013) PGT122 Cryo-EM Structure of a Fully Glycosylated Soluble Cleaved HIV1 Envelope Trimer Lyumkis D1, Julien JP, de Val N, Cupo A, Potter CS, Klasse PJ, Burton DR, Sanders RW, Moore JP, Carragher B, Wilson IA, Ward AB. Science. 2013 Dec 20;342(6165):1484-90.

Crystal Structure of a Soluble Cleaved HIV-1 Envelope Trimer. Julien JP1, Cupo A, Sok D, Stanfield RL, Lyumkis D, Deller MC, Klasse PJ, Burton DR, Sanders RW, Moore JP, Ward AB, Wilson IA.

gp120

Science. 2013 Dec 20;342(6165):1477-83

gp41 BG505 SOSIP Sanders, Moore et al.

Epitopes on Env Trimer PGT128 PG9 V2 apex (glycan) High-mannose Patch (V3-glycan)

VRC01

CD4binding site

gp120gp41 interface gp41 MPER

Peter Kwong, Jonathan Stuckey

8ANC195

In Vitro Neutralization Profiles (190 Diverse strains of HIV-1) CD4bs

V2-glycan

V3-glcan

Interface

MPER

% viruses resistant 4

19

12

4

52

28

51

29

38

45

3

100

IC 8 0 T it e r (  g /m l)

More potent

10

1

0 .1

0 .0 1

0 .0 0 1

6

1

0

E

5 1 T G P

Variation in breadth of coverage Mark Louder, Bob Bailer et al.

8

1

0 1 D G

C

A

P

V

2

R

5

P

-V

1

R

0

C

M

2

-1

6

4

.2

0

5

9 G

7 0

1 T G P

P

4

1 2

6 N

S 3 2 -5 C

0

3

7

B

V

N

R

C

C

1

-L

1

0

7

1

0 .0 0 0 1

Fraction viruses neutralized

Two HIV-1 Antibodies: Improved Potency and Breadth 1.0

VRC07 PGT128

0.8 0.6 0.4 0.2 0.0 0.001

0.01

0.1

ug/ml

1

10

100

Talk Outline  Background on HIV-1 neutralizing antibodies  Antibodies to prevent HIV-1 infection

 Potential role in treatment infection

Long History of Antibodies to Prevent Viral Infections Pathogen

Product Description

Indication

Measles

Concentrated human gamma globulin

Prevention

Polio

Concentrated human gamma globulin

Prevention

CMV

Cytomegalovirus Immune Globulin

Prevention

Hepatitis A

Immune serum globulin (ISG)

Prevention (travel)

Hepatitis B

Hepatitis B Immune Globulin

Post Exposure

Rabies

Rabies Immune Globulin mAb (palivizumab) for prophylaxis of high risk infants

Post Exposure Prevention in High Risk Infants

Varicella Zoster Immune Globulin

Post Exposure

RSV VZIG

Most effective vaccines induce antibodies that neutralize the pathogen

What do we know about antibodies to prevent HIV-infection?  SHIV monkey model: 15 years of data showing that potent mAbs can completely block infection  Many of the new generation mAbs have been tested in this model: VRC01, 3BNC117, PGT121  The level of plasma antibody needed to protect is not too high – can be achieved by infusing physiological dose of antibody (passive transfer)

HIV Antibodies for HIV-1 Prevention What we Don’t Know  No direct evidence that neutralizing antibodies can prevent HIV-1 infection in humans  No data on the level of antibody need to protect  If we passively infuse mAb – don’t know how much or how long the antibody would protect  Does a vaccine have to elicit a neutralization titer of 1:10, 100, or 1:000 to protect?

Vaccine Induced Antibodies The underlying premise for our work on HIV vaccines is that we are aiming to induce broadly reactive neutralizing antibodies (bNAbs): Type of response likely needed for high level protective immunity

Neutralizing antibodies that recognize the majority HIV-1 strains

Vaccine

neutralizing antibodies

Antibody-mediated Prevention Trial (HVTN 703/HPTN 081) Phase IIB efficacy study

 Can infusion of VRC01 mAb, given every 2 months, prevent acquisition of HIV-1 infection in high risk adults  Cohorts: High risk women in S. Africa, and high risk men in Americas

 Importantly: Designed to assess the plasma level of antibody associated with protection

VRC01 mAb: Healthy volunteers Single infusion of 20 mg/kg I.V. into 3 subjects

V R C 0 1 m c g /m l

1000

Plasma levels 100

50 ug/ml

10

10 ug/ml

1 0

10

20

30

40

50

D a y o f s tu d y

VRC, NIAID: Ledgerwood et al, (In press)

60

70

80

90

VRC01 mAb: Healthy volunteers Single infusion of 20 mg/kg I.V.

V R C 0 1 m c g /m l

1000

Month 2

Month 1

100

50 ug/ml

10 ug/ml

10

1 0

10

20

30

40

50

60

70

80

D a y o f s tu d y

Phase IIB prevention study: q 8 week dosing

90

What would clinical study teach us?  No direct evidence that neutralizing • Demonstrate that antibodies can protect antibodies humans from can prevent HIV-1infection infection in humans acquisition of HIV-1 • Establish the level of antibody needed to protect

 No data on the level of antibody need to protect • This sets that stage for our vaccine efforts

Does a vaccine to elicit a serum • Test new vaccines inhave phase I studies: know what kind neutralization titer of 1:10, 1:100 or 1:1000? of antibody response to look for

• Allow faster iterative vaccine studies – pathway to an effective vaccine

Talk Outline  Background on HIV-1 neutralizing antibodies  Antibodies to prevent HIV-1 infection

 Potential role in treatment of infection

Potential use of antibodies for HIV-1Infection  ARV drugs remain cornerstone of treatment  Antibody could augment viral suppression by ARV, e.g., used early after infection  To maintain viral suppression – withdrawal if ARV  To kill cells expressing virus (e.g., ADCC); part of functional cure approaches Infected CD4 cell

mAb 3BNC117 (CD4bs): clinical trial Nature 522, 487–491 (25 June 2015)

HIV-1 infected viremic subjects (off ARV) Plasma viral load after VRC01 infusion

Single infusion of VRC01 (40 mg/kg)

log10 plasma virus (RNA copies/ml)

8 subjects # 20 # 21 # 22 # 23 # 24 # 25 # 26 # 27

5.0 4.0 3.0 2.0 LOD

1.0

-60

-45

-30

-15

0

15

30

45

60

75

90

Days post VRC01-infusion

Lynch, Boritz, Ledgerwood et al.

VRC, NIAID: Unpublished Data

Plasma virus load over time # 20 # 21 # 22 # 23 # 24 # 25 # 26 # 27

Δ log10 virus load (copies/ml)

1.0 0.5 0.0 -0.5 -1.0 -1.5 -2.0

0

10

20

30

40

50

60

70

80

90

Days post VRC01-infusion

6/8 subjects have >10 fold decrease in virus load post-infusion with peak nadir ~ day 9 VRC, NIAID: Unpublished Data

Summary (Treatment)  Antibodies are biologically active – can decrease plasma viral load  Additional studies needed to address whether antibodies can help maintain viral suppression  Key question: Can antibodies impact the viral reservoir?

Future Directions  More antibodies into clinic (n = 2 mAbs)  Antibodies that are both highly potent and broadly reactive  Longer acting antibodies – triple half life; active for up to 6 months  New antibody formats: bi-specific antibodies

Extending half-life

MedImmune YTE mutation

3 - 4 Fold increase in half-life in healthy adults

Maintain > 20 ug/ml for > 6 months

20 ug/ml

Days Means (± standard deviations) of mota-YTE and motavizumab serum concentrations after a single dose (days). Robbie G J et al. Antimicrob. Agents Chemother. 2013;57:6147-6153

Bispecific antibodies VRC07

PGT121

Two different antibody binding arms on one IgG Broader, more potent, less viral escape

Bispecific T-cell engager: CD3 and HIV-1 Mediate cell killing

Infected CD4 cell

Killer T-cell

VRC07

anti-CD3

Summary  Many new HIV-1 antibodies (mAbs) – highly potent and broadly reactive  Potential to prevent HIV-1 infection – studies planned  Potential to complement ARV as part of HIV-1 treatment, especially regarding latent reservoir

Dale and Betty Bumpers

Vaccine Research Center National Institute of Allergy and Infectious Diseases National Institutes of Health

July19, 2015

Antibodies for Prevention and Treatment of HIV-1 Infection

John R. Mascola, M.D. Vaccine Research Center NIAID, NIH