Barney S. Graham, MD, PhDAugust 8, 2014

Clinical Evaluation the HIV-1 CD4 Binding Site-Specific Monoclonal

Antibody VRC01

Structure-basedVaccine Design

Passive Transfer- Direct IgG- Gene vector (AAV)

An Integrated Approach to HIV Vaccine Development

CD4bs

VRC01

Immune pathways ofantibody evolution

10e8

MPER

PG9

V1V2 glycan Trimer11

PGT 128

V3 glycan

Current mAbs are More Potent andBroadly Reactive than Previous mAbs

CAVD David Montefiori (PI)NVITAL Bailer, Louder et al.

0.001 0.01 0.1 1 10 1000.0

0.2

0.4

0.6

0.8

1.0

IC50 cutoff (ug/ml)

Frac

tion

neut

raliz

ed

b12

VRC013BNC117

10E8

2G12

10-1074PG9

190 diverse Env-pseudoviruses

(PGT121)

Since 2009

VRC: Potential Antibodies for Development

gp41 MPER:

10e8

V1V2 Glycan:“None”

CD4 Binding Site:VRC013BNC117

Glycan-V3:10-1074PGT121

VRC07-523VRC13

Clonalrelatives

working on solubility

Potential Antibodies for Development

Clinical Use of HIV Antibodies

• Breastfeeding Infants • High risk young adults• Discordant couples• High risk MSM

• Acute affect on viremia• Treatment interruption/sparing• Impact on viral reservoir• Combined with ARV (functional cure)

Prevention Treatment

Maximize Coverage (breadth)Potent enough to work

Maximize potency Avoid escape

6

Mimicry of CD4 Receptor by Antibody VRC01 and Related mAbs

gp120

CD4VRC01

heavy chain V-domain

Zhou et al. Science (2010); Zhou et al, Immunity (2012)

gp120

CDRH2 loop contact is characteristic of all VRC01-class antibodiesVRC01, PG04, CH31, VRC07, NIH45-46, 3BNC117, 12A12

2F5 Positive Control

VRC 01

No Evidence of Auto-Reactivity

• No antinuclear antibody (ANA) reactivity (HEp-2 cells below)• Negative for clinical anti-cardiolipin assay and ANA• No anti-phospholipid antibody by clinical measurement of aPTT

Barton HaynesJulie Ledgerwood

Immediate aPTT

0

10

20

30

40

50

60

70

Normal Plasma Control

5 mcg/ml50 mcg/ml

VRC02 VRC03 4E10 Synagis b12 ControlVRC01

250 mcg/ml

aPTT

(sec

onds

)

aPTT at 3 dilutions

Number of Viruses Tested

A B C CRF01_AE CRF02_AG CRF07_BC D Other Total25 39 53 16 16 7 8 13 177

Other: AC = 4, ACD = 2, AD = 3 , CD = 3, G = 1

10E8

VRC01

3BNC11

7PG9

10-10

74

PGT121

0

20

40

60

80

100

Perc

ent V

iruse

s N

eutr

aliz

ed

ABCCRF01_AECRF02_AGCRF07_BCDOther

Coverage by Clade

VRC NIAID/NVITAL and Montefiori CAVD (BMGF)

Virus Clade

Percent of Viruses Neutralized at IC50 < 10 mcg/ml

Number of Viruses Tested

A B C CRF01_AE CRF02_AG CRF07_BC D Other Total25 39 53 16 16 7 8 13 177

Other: AC = 4, ACD = 2, AD = 3 , CD = 3, G = 1

A B C

C R F 0 1 _A E

C R F 0 2 _A G

C R F 0 7 _B C D

Oth

e r

0 .0 0 1

0 .0 1

0 .1

1

1 0

1 0 0

IC5

0 (µ

g/m

l)

1 0 E 8

V R C 0 7 -5 2 3

V R C 0 1

3 B N C 1 1 7

1 0 -1 0 7 4

P G T 1 2 1

P G 9P G 1 6

Potency Against Neutralized Viruses

Median IC50 vs neutralized viruses

VRC NIAID/NVITAL and Montefiori CAVD (BMGF)

Origin of VRC07

Donor 45

VRC07

VRC01

Wu et al. Unpublished Data

VRC07-523 Engineered Variant: Improved Potency and Breadth Over VRC07

0 .0 0 1 0 .0 1 0 .1 1 1 0 1 0 00 .0

0 .2

0 .4

0 .6

0 .8

1 .0

IC 5 0 c u to ff (u g /m l)

Fra

cti

on

ne

utr

ali

zed

b 1 2

V R C 0 1

V R C 0 7

V R C 0 7 -5 2 3

~8-fold

IncreasedPotency

M428LN434S

CH2

CH3

• Fc region binds with high affinity to FcRn at acidic pH (<6.5) in endosome• Protects antibody from endosomal degradation • IgG released back into circulation at physiological pH (7.4)• Results in prolonged circulating half life

Neonatal Fc (FcRn) MutationsExtend Half-Life

Zalevsky et al. Nat. Biotechnol, 2010

Mean (± S.D.) of mota-YTE and motavizumab serum concentrations after a single dose (days).

Robbie G J et al. Antimicrob Ag Chemother. 2013;57:6147.

Phase I PK Data (MedImmune) YTE mutation (increases FcRn binding)

M252Y/S254T/T256E3-4-fold increase in half-life

5 months

15 mg/kg

M428LN434S

CH2

CH3

Zalevsky, J., et al. Nat. Biotechnol, 2010. (Xencor)

FcRn Mutations Extend Half-Life

• LS mutation increases affinity for FcRN• Does not affect neutralization or autoreactivity• Does not affect Fcγ binding (ADCC)

Sung-Youl Ko

Half-life

4.7 ± 0.5 days

11.8 ± 4.1 days

Increased Mucosal IgG (VRC01)

Rectal tissue levels

Ko, Pegu et al, Nature, in press.

FcRN

FcRNVRC01

Modeled mAb IgG ConcentrationsPl

asm

a co

nc. (

ug/m

l)

Edmund Capparelli

20 mg/kg q4wks (IV) should maintain > 40 mcg/ml IgG

40 (mcg/mL)

Synagis (PalivizumAb): Infants: 15 mg/kg q4wks (IM)

If FcRn mutation increases half life 2-3 fold, there is a potential for every 3 month dosing

VRC01 Clinical Development

August 2010

IRB Approval: VRC 601

Aug 26, 2013

Jan 19, 2012 May 29, 2013 Aug 7, 2013

2011

VRC01 Pre-IND meeting

IRB Submission: VRC 601

[HIV Infected Cohort]

IND Submission

Publication:Zhou et. al.

Science Aug 2010.

Wu et. al. Science Aug 2010.

Sept 6, 2013

2012 20132010

VRC receives FDA safe to proceed

notification

Sept 30, 2013

VRC 601 First IV Infusion

(1 mg/kg IV)

Nov 12, 2013

VRC 601 First SC Infusion

(5 mg/kg SC)

Oct 1, 2013

IRB Submission:VRC 602

[Healthy Vol Cohort]

Nov 20, 2013

IRB Approval: VRC 602

August 2012

cGMPmanufacturing

at VPP

July 2013

VRC VPP vials VRC01

June 2010

Initiated development of

VRC01 as clinical product

Dec 9, 2013

VRC 602 First Infusions(5mg/kg IV), (5mg/kg SC)

100 mg/ml

Phase IDose Escalation, Safety, and PK Studies

VRC 601: IV or SC in HIV-Infected Adults

Group N = Days 0 and 28

1 5 1 mg/kg IV

2 5 5 mg/kg IV

3 5 5 mg/kg SC

4 5 20 mg/kg IV

5 5 40 mg/kg IV

17 clinical visits and 28 PK blood draws per subject

Group N= Days 0 and 28

1 5 5 mg/kg IV

2 5 20 mg/kg IV

3 5 40 mg/kg IV

4 9 5 mg/kg or Placebo SC

16 clinical visits and 28 PK blood draws per subject

VRC 602: IV or SC in Healthy Adults

19

Phase I PK Data (healthy volunteers)

VRC, NIAID: Unpublished Data

0 1 0 2 0 3 0 4 0 5 0 6 0

1

1 0

1 0 0

VR

C0

1 (

ug

/mL

)

0 10 20 30 40 50 601

10

100

Time (days)

VRC0

1 (u

g/m

L)

5 mg/kg I.V.

5 mg/kg S.C.

VRC 602 20 mg/kg IV(Healthy volunteers)

VRC, NIAID: Unpublished Data

0 10 20 30 40 50 6010

100

1000

Time (days)

VRC0

1 (u

g/m

L)

3 Subjects: 20 mg/kg I.V.

40 mcg/ml

Similar data in ARV-suppressed HIV-infected volunteers (VRC 601)

VRC 602 40 mg/kg IV(Healthy volunteers)

0 1 0 2 0 3 0 4 0 5 0 6 01

1 0

1 0 0

1 0 0 0

T im e p o in t (d a y s )

VR

C0

1 (

ug

/mL

) 4 0 m g /K g IV

V R C 6 0 2

HVTN 104

• N=64• Healthy uninfected adults 18-50 yo• Primary objectives are safety and pharmacokinetics• 12 weeks of followup after final dose

Kenneth Mayer, MD – Principal Investigator

Gp 3 20 40 IV 5 sc 5 sc 5 sc 5 sc 5 sc 5 sc 5 sc 5 sc 5 sc 5 sc 5 sc 5 sc

Months 0 1 2 3 4 5 6

N mg/kg IV=intravenous sc=subcutaneous

Placebo 4 IV sc sc sc sc sc sc sc sc sc sc sc sc

Gp 2 20 40 IV 40 IV 40 IV Gp 1 20 40 IV 20 IV 20 IV 20 IV 20 IV 20 IV

Predicted levels of VRC01 in HVTN 104

Clinical Development Plans for Prevention

VRC: Phase I safety and PK in

HIV-infected adults

VRC: Phase I safety and PK in

healthy HIV-uninfected adults

IMPAACT: Safety and PK in high-risk US infants

Route: sc

IMPAACT: Phase IIbin high-risk

breastfeeding infants

HVTN: Multi-dose safety and PK in US adults

Route: IV and sc

Phase IIbefficacy in

high-risk adults

HIV-uninfected

HIV-infected

AdultsPMTCT

Phase1

1

1b

2b

25

Proj

ecte

d Ph

ase

I and

II V

RC

01 C

linic

al T

rials

Year

VRC mAb VRC01 Clinical TrialsProjected Activity 2013-2017

2013 2014

Phase I: HIV- AdultsHVTN 104: US

2015

Phase I: HIV+AdultsNIAID Intramural: VRC 601

Phase I: Infants of HIV+ Mothers IMPAACT P1112: US

Phase I: HIV- AdultsNIAID Intramural: VRC 602

Phase I: HIV+ Adults Acutely Infected with ATIMHRP RV397: Thailand

2016 2017

HIV- Negative Subjects

HIV+ Positive Subjects

Phase II: Infants of HIV+ MothersIMPAACT Network: International

Phase I: HIV+ Adults Acutely Infected MHRP RV398: Thailand, Kenya,Tanzania, Uganda

Phase I: HIV+ Adults ATIACTG A5340: US

Phase I: HIV Long Term+ AdultsACTG A5342: US

AcknowledgementsJulie LedgerwoodMary Enama Ingelise GordonEleanor WilsonLasonji HolmanSarah PlummerCynthia Starr HendelLaura NovikPamela CostnerKathy ZephirFloreliz MendozaJamie SaundersSandra SitarBrenda LarkinGalina YamshchikovOlga VasilenkoIris PittmanNina BerkowitzBrandon WilsonPernell WilliamsAlisha KabadiCarmencita Artis

Clinical Trials Program

27

AcknowledgmentsMascola labNicole Doria-RoseXueling WuCharlene WangRebecca LynchLillian TramSijy O’DellStephen SchmidtNancy LongoMark LouderKrisha McKee

CHAVI Mattia BonsignoriGeorgia TomarasTony MoodyDavid MontefioriJohn A CrumpSaidi H. KapigaSam E. Noel Myron CohenBart Haynes

Wyatt lab (Scripps)Yuxing LiFeng YuBimal Chakrabarti

(former) Nabel labZhi-yong YangLing XuLan WuXuejun ChenAmar PeguRebecca RudicellKevin SaundersSung-Youl KoWei ShiJeffrey Boyington

CTPJulie LedgerwoodMary EnamaIngelise GordonLaura Novik

Univ of WashingtonBill Schief

Koup labBob BailerLaurie Lamoreaux

IAVI and NACMelisa SimekPat FastLaura WalkerSanjay PhogatWayne KoffDennis Burton

Kwong labTongqing ZhouJiang ZhuLarry ShapiroBaoshan ZhangIvelin GeorgievYoung Do KwonGilad OfekYongping Yang

NISCHolly ColemanBrian SchmidtMorgan ParkJim Mullikin

HVTN & SCHARPScott Hammer (Columbia)Larry CoreyJulie McElrathSteve SelfPeter GilbertKen Mayer (Harvard)

Roederer labSteve PerfettoRichard NguyenDavid AmbrozakKathryn FouldsMitzi Donaldson

Rao LabJohn-Paul ToddAlida AultSaran BaoAlyse Zajac

DAIDSCarl DiffenbachAlan Fix

LIR, NIAIDMark ConnorsJinghe Huang

28