does atlas have broad shoulders? - genocea biosciences€¦ · · 2017-10-25does atlas have broad...
TRANSCRIPT
Does ATLAS have broad
shoulders?
Jean-Luc Bodmer Vaccine Technology V, Playa del Carmen
The Need for and Challenges of T Cell-Enabled Vaccines
• C. trachomatis
• CMV
• Dengue fever
• Gonococci
• HSV-1
• HSV-2
• Malaria
• Pneumococci
• Pseudomonas
• S. aureus
• Tuberculosis
Pathogens where T cells contribute to
protection
T cells pose new challenges
Impact on discovery
• Up to 1,000X increase in potential targets
• Diversity of human T cell responses – Greater variability than
antibody
– Difficult to model in animals
• Time, cost
• Less predictive
power
A large need . . . but significant discovery hurdles
2
Potential T cell antigens – a vastly increased pool of
candidates
David Goodsell watercolor – cross-section of E. coli http://www.hhmi.org/bulletin/winter-2013/structural-revolution
Antibody targets limited to: • Surface proteins & carbohydrates • Secreted proteins & toxins
How do you define which targets are the best antigens for T cell responses?
T cells targets comprise a much larger repertoire: • Any protein or pieces thereof expressed on or in a pathogen • Dozens to thousands of potential targets
3
Antigen Recognition: Greater Variability in presentation
• There are nearly 2000 known alleles of HLA (MHC) genes
• Grouped into HLA supertypes – each HLA molecule within a supertype binds essentially
the same peptide epitope
– MHC-I :HLA-A1, -A2, -A3, -A24, -B7, -B27, -B44, -B58, -B62
– MHC-II :HLA-DQ1, -DQ2, -DQ3, -DQ4, -DQ5 (95% coverage)
• Antigen processing, presentation and recognition is highly diverse and depends on the
genetics of each subject.
http://sph.bu.edu/otlt/MPH-Modules/EH/EH_Immunity_B/BindingAntigenEpiptopes.png
Antibody T cell
4
Final Ag
Vaccine
ATLAS™: Antigen Lead Acquisition System
Further in vivo
validation and development
Antigen ranking
High throughput screening
Full length, full
proteome libraries
Clinical cohorts
Full Proteome Top Candidates Leads
5
6
ATLASTM Screening Technology Flowchart
7
ATLASTM: Screening for responses against CD4+ T cells
8
ATLASTM: Screening for responses against CD8+ T cells
Addressing intractable diseases at Genocea
9
GEN-004: Streptococcus pneumoniae
Inhibition of mucosal colonization
GEN-005: Plasmodium falciparum
Elimination of infected hepatocytes
GEN-001: Chlamydia trachomatis
Elimination of infected epithelial cells
GEN-003: Herpes Simplex Virus-2
Elimination of infected epithelial cells
Genome Size – Probing the Proteome of diverse pathogens
with ATLAS screening libraries
10
Pathogen Disease(s) # Clones
Expression
Rate
Program
status
Herpes Virus
Simplex 2 Genital Herpes 85 100% Phase Ia/II
Chlamydia
trachomatis
PID, urethritis,
lymphogranuloma
venereum
960 97% Pre-clinical
Plasmodium
falciparum Malaria 1189 88% Antigen ID
Streptococcus
pneumoniae
(otitis media, pneumonia, sepsis, meningitis)
2,218 95% Phase I/II pneumococcal disease
GEN-003 (HSV-2 Immunotherapy)
GEN-004 (Pneumococcus Px)
GEN-002 (HSV-2 Px)
GEN-001 (Chlamydia)
Malaria
Discovery
Genocea’s Pipeline of T Cell-Enabled Product Candidates
11
Pre-clinical Phase 1 Phase 2 Phase 3
Oncology
GEN-003: Therapeutic Vaccine against HSV-2
• Lifelong sexually transmitted disease – Painful, recurrent genital ulcers
– Significant emotional distress
• Public health epidemic – 500 million people infected worldwide (16% of U.S. adults)
– Contributes to transmission of HIV-1
– Serious complications from maternal-to-infant transmission
• Standard of care (oral anti-viral drugs) has limitations – Incomplete control of recurring ulcers
– Continued risk of transmission
– Compliance burden to maintain effect
12
• Reduce viral shedding: – To improve
symptom control – To reduce
transmission risk
• Convenient dosing regimen
• Novel mechanism of action
GEN-003 Composition
GEN-003: A Novel HSV-2 Therapeutic Vaccine Candidate
Intervening against HSV-2
Matrix- M2
adjuvant
T Cell Antigen
ICP4.2
B Cell Antigen
gD2DTMR
GEN-003 Proposition
Novel T cell antigen prioritized via ATLAS
Points of potential T cell intervention
Point of potential B cell intervention
Virus moves
from nerve cell
to skin and
mucosa
13
GEN-003: Highly Significant, Durable Impact on HSV-2
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
Baseline After dose 3 After 6 months
14
10 µg
100 µg
30 µg
Placebo
Proteins only
*** ***
***
Genital Lesion Rate (a)
*** = p<0.001 (a) Normalized so that rate at baseline = 1
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
Baseline After dose 3 After 6 months
*** ***
***
Viral Shedding Rate (a)
10 µg
100 µg
30 µg
Placebo
Proteins only
GEN-004: Significant Need for a New Vaccine
• Pathogenic bacterium causing pneumonia, sepsis,
meningitis, otitis media
– A leading cause of infectious disease mortality
• Global vaccine market value of $5 billion in 2013
– Led by Prevnar/Prevenar (Pfizer): $4 billion
• Commercially available vaccines sub-optimal
– Limited serotype coverage
– “Non-vaccine serotypes” increasing in incidence
– Manufacturing complexity
15
Natural clearance (TH17 CD4+ T cell-mediated)
Prevnar et al (antibody-mediated)
Intervening against
Pneumococcus
http://www.ohiohealth.com/
http://www.childrenscentralcal.org/HealthE/P02
948/Pages/P02950.aspx
GEN-004 composition
Alum
adjuvant
Novel T cell antigens
prioritized via ATLAS
T Cell
Antigen
SP1912
T Cell
Antigen
SP2108
T Cell
Antigen
SP0148
• Cover all pneumococcus serotypes
• Reduce colonization via TH17
• Complement antibody
MoA
GEN-004 Proposition
16
GEN-004: T Cell-Enabled Impact on Colonization
0
50
100
150
200
250
Alum GEN-004 WCV
Am
ou
nt
of
Co
lon
iza
tio
n
(CF
Us
)
Parenteral administration
WCV = non-encapsulated killed whole bacteria
+ Alum
p<0.001 p<0.001
Nasopharyngeal colonization after 3 immunizations
GEN-004: Effect in Mouse Colonization Model
17
GEN-004: Phase 1 Trial
• Patients: 90 healthy adult volunteers ages 18-50
• Trial design: – Randomized, double-blind, dose-escalation
– 5 dosing groups of ~18: • Placebo
• Proteins only
• GEN-004 (10 µg of each protein + 350 µg alum)
• GEN-004 (30/350)
• GEN-004 (100/350)
– 3 doses at 1 month intervals
• Objectives: – Safety and tolerability
– Immune responses: especially T cell (IL-17)
18
Potentially the first protein subunit pneumococcus vaccine to demonstrate TH17 response
GEN-001: An elusive vaccine against Chlamydia
trachomatis
• C. trachomatis development cycle poses challenges
to development of immune response
• Compelling evidence that both B cell and T cell
immunity play a role in developing protection
• A vaccine that effectively stimulates both B cell and
T cell responses to specific C. trachomatis antigens
may help confer protection
19
GEN-001: Cohort-based screening identify a small number of Ag
0
5
10
15
20
25
30
35
40
45
1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39
Per
cen
t R
esp
on
der
s
Clone (arbitrary)
** **
CD4+
0
5
10
15
20
25
30
35
40
45
1 4 7 10 13 16 19 22 25 28 31 34 37 40 43 46 49 52
Per
cen
t R
esp
on
der
s
Clone (arbitrary)
Protected
Unprotected
** **
CD8+
**p<0.05; all others p<0.1
(Spont. resolution + Exposed)
(Persisting Infection + PID)
20
15
17
19
21
23
25
27
29
31
33
35
0 50 100 150 200
Pe
rce
nt
Re
spo
nd
ers
Clone (arbitrary)
CD8
CD4
GEN-001: Immunodominance and Protection Do Not
Correlate
“Protective” Antigen
TFI Antigen
+
+
21
Co
py
Nu
mb
er
DN
APBS
UVEB
GB04
2
GB04
2 +
MM
GB04
4
GB04
4 +
MM
10
100
1000
10000
100000 p<0.065
NS
• Design
– Mice immunized with GB042 (top CD4 antigen) and GB044 (TFI associated immunogenic antigen)
– Quantitative PCR to detect Chlamydia DNA in oviducts
• Results
– GB042 significantly decreased bacterial burden in the oviducts
– GB044 increased bacterial burden in oviduct
• Takeaway: “Bad” antigens associated with pathology do not clear Chlamydia even if they are immunogenic
GEN-001: Pathology-associated Antigens May Not Protect
22
GEN-005: Malaria, a global Unmet Medical Need
• Endemic to over 100 nations and territories
– Over 200 million cases annually
– Estimated 600,000 deaths annually.
– 90% of these deaths occur in sub-Saharan Africa, (mostly children > 5yo)
– ~ $12B in annual expenses in Africa
• Prevention
– Insecticide-treated mosquito nets (ITNs), indoor spraying with residual insecticides
– Draining of swamps / marshes
– Chemoprophylaxis available, but cumbersome.
• Standard of care
– Artemisinin-based combination therapy (ACT, current std of care)
– Rise of Antimalarial drug resistance
• Vaccines against Malaria
– There are currently no licensed vaccines against malaria………….
24
GEN-005 : targeting the hepatic stage of P. falciparum
Plasmodium in liver
5-16 days after
mosquito bite Plasmodium in
bloodstream for
~30 min
Plasmodium in
blood 17-20 days
post bite.
Recurrent fevers
(1-3 days)
Liver Stage: CD8+ T-Cell
25
GEN-005 in the context of the MVI portfolio
12
14
1
RTS,S/AS01E-GSK CSP based
Phase III trial ongoing: 25%~50%
protection(Oct, 2013 updated)
Strong antibody response, lack of
cellular response
Prevent and
reduce
clinical
illness
No clinical
symptoms Block
transmission
ATLAS screening
GEN-005
26
GEN-005: pre-erythrocytic Proteome Library Design
Complete Proteome
5,300 ORF
Build 3:
+430 ORF
Build 2:
+288 ORF
Build 1:
901 ORF
27
Human Plasmodium in
human liver cells
Murine Plasmodium
in murine liver cells
GEN-005: Clinical cohorts exhibiting sterilizing immunity
RAS
radiation-attenuated sporozoites
immunization by mosquito bites, large # infected bites
CPS
Live non-attenuated sporozoites
Immunization by mosquito bites, small # infected bites
Administered during chloroquine prophylaxis
PfSPZ
Cryo-, purified radiation-attenuated sporozoites
Immunization by intravenous injection (IV), high dose
All three approaches have been shown to induce
100% sterilizing immunity against Controlled
Human Malaria Challenges (CHMI)
28
GEN-005: Genocea’s Screening Plan
Sample Set Institution Samples Library scale Significance Completion
PfRAS NMRC
(Richie) 24 735 ORF
Vaccination, 50% sterilizing immunity (19??)
3Q2013
Endemic (US immigrants)
ASC (Bronx, NY)
100 735 ORF Natural Immunity 3Q2013
CPS RUNMC
(R. Sauerwein) 42 132 ORF
Vaccination, 100% sterilizing immunity (2011)
2Q2014
Endemic (Mali)
NIAID (P. Crompton)
40 735 ORF Natural Immunity 3Q2014
PfSPZ NIAID, Sanaria
(Seder/Hoffman) ~40 ~1,000 ORF
Vaccination, 100% sterilizing immunity (2013)
4Q2014*
PfSPZ NHP NIAID
(Seder) TBD ~1,000 ORF
Peripheral vs. Hepatic responses
4Q2014
PfRAS (IMRAS) NMRC, BMGF 88 >1,500 ORF Vaccination (2014-15) 4Q2105
CPS RUNMC
(R. Sauerwein) 20 >1,500 ORF Vaccination (2015) 2Q2015
29
GEN-005: screening of 8 RAS patients provisionally
identifies novel candidates not previously considered
30 June 24, 2014
Confidential
Gene Class N Percentage
DNA & RNA metabolism 15 (12.4%)
Signaling 8 (6.6%)
Unknown or hypothetical 51 (42.1%)
Cellular Transactions 21 (17.4%)
Energy Metabolism 19 (15.7%)
Structural 3 (2.5%)
Pathogenicity 4 (3.3%)
Genocea’s ATLASTM platform…
• Has broad shoulders – Can identify new Antigen Candidates (GEN-003/4/1)
– Can be customized to address various effector mechanisms (Cytotoxic CD8 T cells, Th1 CD4, Th17 CD4).
– Has generated POC in Phase Ia clinical trials (GEN-003)
• Can do the heavy-lifting – The team at Genocea has successfully built expression libraries
containing FL ORF from organisms as divergent as viruses, bacteria, protozoans and now human.
– Many hundred samples were successfully screened
– Two programs completed pre-clinical development and PhI manufacturing campaigns
• Can make a difference
31
Acknowledgements
32
Richard Malley
Kristin Moffitt
Yingjie Lu
GEN-003: HSV-2
GEN-003-001 trial participants
University of Washington
Westover Heights Clinic
Indiana University School of Medicine
Center for Clinical Studies, Houston TX
Center for Clinical Studies, Webster TX
IND 2 Results
University of Alabama Birmingham
Cincinnati Children’s Medical Center
Rho, Inc.
William Geisler Edward W. Hook
Amy Scurlock Suzanne Trupin
Jeff Klausner
Toni Darville
CAPT Thomas Richie
CAPT Eileen Villasante
Joao Aguiar
Noelle Patterson
Jessica Bolton
Stefan Kappe
Alexis Kaushansky
Kim Nichols
GEN-005: Malaria GEN-001: Chlamydia
GEN-004: S. pneumoniae Robert Seder
Andrew Ishizuka
Peter Crompton
Robert Sauerwein
Else Bijker
..And the team
at Genocea…
Acknowledgements
33 June 2014
Summer 2013
Winter 2011