DEVELOPMENT OF

MONOCLONAL

ANTIBODIES

FOR HIV TREATMENT

AND CURE Co‐sponsored by

National Institute of Allergy and

Infectious Diseases and

Bill and Melinda Gates Foundation

Development of Monoclonal Antibodies

for HIV Treatment and Cure • Venue

• Wednesday, June 3 ‐ Thursday, June 4, 2015, NIH,

Rockville, Maryland

• Purpose

• Bring together key players to discuss the development

pathway for broadly neutralizing monoclonal antibodies

(bNAb) and bNAb‐containing regimen for the treatment

and cure of HIV.

Antibody research

• 100s broadly neutralizing antibodies (bNAbs) identified since

2009 • Work against majority of HIV strains

• Target limited number of sites on HIV surface

• Direct transfer of antibodies—passive immunization—being

tested as prevention, treatment, part of cure • Early clinical trials show safety, tolerability, significant viral reduction among HIV-

positive participants

• Larger-scale studies planned for safety, dosing, efficacy

• Hope to increase potency of bNAbs and duration of responses in humans

2F5, 4E10, 10E8 Membrane proximal region

2G12, PGT Abs Carbohydrate CD4 binding site

1b12, VRC01, VRC02, VRC03, VRC-PG04, HJ16, CH30-CH34

V1/V2 PG9, PG16, CH01-CH04

BnAb Antibodies:

Dennis Burton,

Herman Katinger,

Michel Nussenzweig,

John Mascola, Bart

Haynes, Robin Weiss Adapted from William Schief

Development of Monoclonal Antibodies

for HIV Treatment and Cure • Welcome and Opening Remarks

• Anthony Fauci, National Institute of Allergy and

Infectious Diseases

• 73 bnAbs discovered

• Applications:

• Preventive Vaccine

• Treatment

• Cure, defined as sustained non-active viral replication

• Potential to inform non-vaccine prevention

Topic 1 - bNAb: State‐of‐the‐art

• Overview and potential roles for bNAb in HIV

treatment and cure, Dennis Burton, The Scripps

Research Institute

• Discussed coverage and potency of bNAbs

• Lessons learned: protection, limited therapeutic effects, target

regions, unusual features

• Some show incomplete neutralization phenomenon

• Engineering bNAbs

• Enhance neutralizing potency

• Increase Ab half-life

• Enhance effector function

Topic 1 - bNAb: State‐of‐the‐art

• Development of VRC01 and other bNAb, Barney Graham, National Institute of Allergy and Infectious Diseases • VRC 601 the VRC01 Trial opened in 2013

• This is a dose-escalation study to examine safety, tolerability, dose and pharmacokinetics of VRC01. The hypothesis is that VRC01 will be safe for administration to HIV-1 infected adults by the intravenous (IV) and subcutaneous (SC) routes and will not elicit hypersensitivity reactions. Samples will be collected to learn if VRC01 is detectable in mucosal secretions and blood of participants and how long VRC01 can be detected in the blood after it is given.

• 4 dose escalation groups for IV administration: 1 mg/kg, 5 mg/kg, 20 mg/kg and 40 mg/kg. There is 1 group for SC administration at 5 mg/kg. Participants will receive two infusions of VRC01 with about 1 month between doses. Infusions are administered in an inpatient unit and an overnight stay at the NIH Clinical Center is required. Study participation lasts for 24 weeks. Participant health and effect on CD4 count and HIV viral load will be monitored.

• Study effects in viral reservoir

• Potential for inter-network collaborations (IMPAACT, HVTN, ACTG)

• Other bNAbs are being studied to potentially treat acute infection

Topic 1 - bNAb: State‐of‐the‐art

• Development of 3BNC117, 10‐1074 and other bNAb,

Michel Nussenzweig, The Rockefeller University

• Roles of bNAbs on HIV-1 prevention

• Passive protection

• PEP, early treatment of HIV-1

• Chronic Therapy

• Engage the inmune system, clear infected cells

• Latent HIV-1 reacts to bNAbs

• 3BNC117

• Single infusion 10mg/kg

• HIV-, half-life of 17 days

• HIV+ half-life of 10 days

• At 30mg/kg shows drop in viremia at 8 weeks

Topic 1 - bNAb: State‐of‐the‐art

• Development of PGT121 and other bNAb, Dan

Barouch, Beth Israel Deaconess Medical Center

• PGT121 demonstrated protection in SHIV

• Viral load rebound as related to early ART initiation + PGT121

• Reduction in proviral DNA

• Combination with reservoirs activators will be beneficial

• A PGT121 single infusion + ART had some effect on but not

prevented viral rebound

• Community concerns: How to initiate early ART post-infection?

• Other studies are assessing the protective efficacy of PGDM1400

in rhesus monkeys

• May be more potent in-vivo

• May need reduced doses

Topic 2

Novel antibody‐based therapeutics • Bi‐specific antibodies, David Ho, Aaron Diamond AIDS

Research Center

• Enhanced potency and breath

• Roche’s CrossMab technology to generatebi-specific mAbs

• Potential for passive inmunization

• Library of >100 engineered Abs

• 10E8/Imab, 10E8/P140 : activity is bettr than making a mixture of

parental Abs

• Experiments with Hu-mice show protection after repeated

challenges

• Improvements at Glycan52, LS and YTE mutations

Topic 2

Novel antibody‐based therapeutics • Pipeline of new mAb and other targeting formats,

Dimiter Dimitrov, National Cancer Institute

• Bi-specific of multivalent proteins

• Fusion proteins of increased efficacy

• Elimination of HIV-1 infected cells

• Potent activity in PBMC

Topic 2

Novel antibody‐based therapeutics • AAV‐expressed eCD4‐Ig, Michael Farzan, The Scripps

Research Institute

• AAV – adeno-associated virus vectors can stably express

concentrations over 3-5 years

• Challenges of AAV delivered bNAbs

• Not broad enough for immunotherapy

• 100% isolates neutralized, including SIV and HIV-2

• May be used as vaccine alternatives

Topic 3 - Lessons from other fields

• Experience developing modified mAb for RSV, Pam

Griffin, MedImmune

• MEDI557, Motavizumab YTE, first study in humans at various

concentrations

• MEDI8897, next generation, first time study in healthy volunnteers

Topic 3 - Lessons from other fields

• Experience developing a two mAb treatment cocktail

for rabies, Jerry Sadoff, Janssen Infectious Diseases and

Vaccines, Johnson & Johnson

• CR57 and CR4098, fully human IgG Abs

• Replacement products for HRIG

• Robust manufacturing process

Topic 4 –

Choosing bNAb combinations • bNAb effector functions, Galit Alter, Ragon Institute

• Fc effectors function for treatment and cure

• Ask if Abs are recognized at initial infection or at spread?

• Neutralization alone is not sufficient

• NK activity is needed

• Killing requires the recruitment of innate immune cells

• Identify best Env targets

• Evidence of Abs binding can kill activated cells

• Fc function can be customized to target tissue repair

Topic 4 –

Choosing bNAb combinations • Choosing bNAb to prevent escape, Bette Korber, Los

Alamos National Laboratory

• Three or more Abs may be needed to realice full benefit

• Abs candidates:

• MPER; V2glycan; V3glycan, CD4bs

Topic 4 –

Choosing bNAb combinations • Using dose response curve slopes to assess bNAb

potency and breadth, David Montefiori, Duke University

Medical Center

• Statistical analysis

• Factors to consider:

• Potency; Breadth; Half-life; Tissue distribution; Safety; Immunosenescity

• DRCS sets class-specific limits on inhibitory potential

• Missing dimension on drug resistance

• Slope defines therapeutically relevant bNAbs potency

Topic 4 –

Choosing bNAb combinations • Using animal models to select bNAb, Malcolm Martin,

National Institute of Allergy and Infectious Diseases

• Properties of SHIV

• Sustained levels of replication

• CCR5 and CCR5 mutation

• Induce OI

• Cross-reactive nAbs

• Antibody mediated immunotherapy of macaques with chronic infected

SHIV suppresses viremia

• Can treat with nAbs to reduce viral reservoir

• Combine 3BNC117 plus 10-1074, 3 weekly IV injections

Topic 4 –

Choosing bNAb combinations • FDA perspective on co‐development of mAb for use in

combination, Jeff Murray & Kathleen Clouse, Food and

Drug Administration

• Proponents can contact FDA early in the development process

• Product characterization

• In vitro efficacy data

• Product Quality Review Focus

• Suitability of expressing vectors and cell substrates

• Virology review requirements

• Immunogenicity concerns

• Guidance documents FDA/CDER 2013, Stability Testin of Drug

Substances

Topic 5 - Panel session:

Choosing bNAb combinations • Moderators:

• John Mascola, Vaccine Research Center, NIH

• John Mellors, University of Pittsburgh

• Panelists:

• Galit Alter, Ragon Institute

• Dan Barouch, Beth Israel Deaconess Medical Center

• John Corbin, Gilead Sciences, Inc.

• Hana Golding, Food and Drug Administration

• David Montefiori, Duke University Medical Center

• Sarah Schlesinger, The Rockefeller University

Topic 5 - Panel session:

Choosing bNAb combinations • What are the desirable profiles for bNAb combinations?

• What bNAb characteristics may differ for treatment and

cure?

• What preclinical data should be used to make decisions to

pair bNAb for treatment? For cure?

• What roles should animal models play in deciding which

bNAb to pair for treatment? For cure?

• What clinical data should be used to make decisions to

pair bNAb for treatment? For cure?

Topic 5 - Panel session:

Choosing bNAb combinations • Some Answers

• Bridge to Adherence

• May be approved for PEP

• Ease of drug provision mechanisms and timing

• Assays to determine best mAbs combinations

• Counteraction of toxicities

• Economic drivers of mAbs development

• ART targeted replicant virus

• Low-level viremia might contribute to inflammation

• Env escape variances in chronic infected individuals

• Community concern: Are bNAbs the “magic bullet”?

• Consider mutations that come from acute vs chronic infection

Topic 6 - Manufacturing mAb

• Manufacturing mAb: State‐of‐the‐art, James Thomas,

Just Biotherapeutics, Inc.

• 30 years of progress in biotherapeutics

• Development of large-scale facilities to produce mAbs at low cost

• Integration of four core elements:

• Molecule

• Process

• Product

• Plant

Topic 6 - Manufacturing mAb

• Panel session: Development and manufacturing issues

• Moderators: • Steve Hadley, Bill and Melinda Gates Foundation; Thomas Hassell,

International AIDS Vaccine Initiative

• Panelists: • James Thomas, Just Biotherapeutics, Inc.; Tim Kelly, KBI Biopharma,

Inc.

• How can we modify bNAb to extend half‐life, increase functional activity, and limit immunogenicity?

• How can we ensure bNAb coming out of research are optimized for further development/manufacturing?

• How can we rapidly manufacture small lots of bNAb for experimental medicine studies?

• How can we reduce the cost of bNAb for large‐scale deployment?

• How can we co‐formulate bNAb for combination use?

Topic 7- Designing clinical trials

• Session A: Designing clinical trials for HIV treatment

• Moderators: • Daniel Kuritzkes, Brigham and Women's Hospital/Harvard Medical School; Grace Aldrovandi,

Children’s Hospital Los Angeles

• Panelists: • Roy Gulick, Weill Cornell Medical College; Jeffrey Jacobson, Drexel University College of

Medicine; Jeff Murray, Food and Drug Administration; Kimberly Smith, ViiV Healthcare; Summer

Zheng, Harvard T. H. Chan School of Public Health

• What populations should be studied?

• What study designs are preferred?

• What is the desired sequence of trials?

• What trial designs could accelerate clinical development?

• What endpoints are needed (assays; preferred time‐points for each assay)?

• How do we determine whether bNAb have unique benefits versus ART?

• Are there specific pediatric considerations?

• How can animal models best inform trial design issues?

Topic 7- Designing clinical trials

• Answers

• Agreement in the Prevention potential

• Populations to be studied:

• Must be convenient, accessible, cost-effective

• Focus on acute infection and suppressed viremia

• Individuals with treatment failure

• Consider long-term side effects

• chronic unsuppressed individuals

• Heavily treated patients as participants?

• Preferred Study designs

• Phase 1 for dose, dosing schedule

• Phase 2 and 3: Adaptive design

• Offering a suppressive regimen will be a strong incentive

• Treatment interruption

• Reach hard to treat populations

Topic 7- Designing clinical trials

• Answers

• Endpoints

• Assays to identify early immune responses

• VL

• Treatment failure

• Long-term complications of ART

• Opportunistic Infections

• CNS

• Genital track escape

• Animal models

• Proof-of-Concept

• Maintain suppression’

• Safety issues in poly-activity

• Pk issues

• Ab combinations

Topic 8 –

Panel session: Industry round table • Panelists:

• Wade Blair, Merck; Romas Geleziunas, Gilead Sciences, Inc.;

George Hanna, Bristol‐Myers Squibb Company; Scott Koenig,

MacroGenics; Sanjay Phogat, Sanofi Pasteur; John Pottage, ViiV

Healthcare; Andrew Spaltenstein, GlaxoSmithKline

• What role does industry want to play?

• What data would drive industry’s interest in this field?

• as an active participant in the research

• as a driver of the research

Topic 8 –

Panel session: Industry round table • Answers

• Interest in the field

• Prevention, eradication

• Challenges of measuring reservoirs

• Translational science offers promise

• Develop platforms for bNAbs and non-bNAbs

• Vaccines development

• Collaborations

• Prevention en-route to cure

• Potential for LAA

• Work together with Community from the beginning

Future priorities

• Continued clinical research

• P5 strategy – large-scale trials following RV 144 results in South Africa and Thailand

• Clinical trials of vaccine using “mosaic” (cross-clade) immunogen by Janssen (division of

J&J)

• Advancement of candidates/strategies currently in smaller-scale trials, depending on

results

• Further bNAb research—pre-clinical discovery and advancement of current

bNAbs in clinical trials

• Continued identification of novel vectors, adjuvants and other strategies for

improved candidates

What is needed now?

• Monitor timelines of clinical trials, especially delays and the reasons

for them

• Ensure diversity of approaches beyond pox-protein strategy, exploring

novel directions for vaccine design

• More stakeholder involvement, e.g., on trial design, standard of

prevention/care, decision-making on moving candidates through the

clinical pipeline

Community Involvement

• bnAbs is the new frontier towards treatment and cure

• Complex concepts; might be difficult to explain in lay

terms

• Understand the science behind bnAbs

• Be ready to identify long-term benefits

• But also the risks

• Altruism: Be clear to potential participants that this new

research may not have immediate benefits for them

Key resources

• AVAC: www.avac.org/vaccines

• Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID)

o At Duke: www.chavi-id-duke.org

o At Scripps: www.cavi-id.org

• Collaboration for AIDS Vaccine Discovery: www.cavd.org

• Global HIV Vaccine Enterprise: www.vaccineenterprise.org

• HIV Px R&D Database (PxRD): www.data.avac.org

• HIV Vaccines & Microbicides Resource Tracking Working Group: www.hivresourcetracking.org

• HIV Vaccine Trials Network (HVTN): www.hvtn.org

• International AIDS Vaccine Initiative (IAVI): www.iavi.org

• Military HIV Research Program (MHRP): www.hivresearch.org

• NIAID: www.niaid.nih.gov/topics/hivaids/research/vaccines/Pages/default.aspx

• NIH Vaccine Research Center (VRC): www.vrc.nih.gov

• Pox-Protein Public-Private Partnership (P5): www.hivresearch.org/media/pnc/9/media.749.pdf

Closing remarks

• Carl Dieffenbach, National Institute of Allergy and

Infectious Diseases

• Don’t forget your past

• Take advantage of what we have today

• Don’t forget the future

Thank you!

• Morénike Giwa-Onaiwu & Paul Klees

• GCAB & CSS

• All participants & community

• Angel L Hernandez

• GCAB-CSS