Pandemic Prevention Platform (P3) Proposers Day West: Lightning
Talks
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Aridis
MabIgX Technology Aridis Pharmaceuticals, Inc5941 Optical Court
San Jose, CA95138
Human convalesce
nt donor
B-cell fusion &
screening
Cell line characteriz
ation
GMPmanufacturing
Human convalesce
nt donor
B-cell fusion &
screeningManufacturing
MabIgX® Process – stable B-cell fusion cell lines
• FAST – Reach Phase I in 6-8 months• SAFE – Fully human mAbs• POTENT – mAb optimized by human immune system• APPROVED – 2 mAbs passed Phase IIa clinical (FDA/EMA)
P3 MabIgX® Improved Process
Take cell line from screening directly to production run: <60 days• Concurrent screening of mAbs, upscale & cell line testing• Single cell/microfluidics technology
In-vivo potency optimization of mAb (human immune system) prior to fusion
Anti-infective immunotherapy using human monoclonal antibodies is a promising therapeutic option to treat infectious disease outbreaks
Conventional mAb Discovery & Development Process: 18-24 monthsImmunizatio
n of miceB-cell
screeningAntibody
(genome)sequencing
Humanization& vectorconstruction
Antibody vector transfection &
clonal selection
Cell line process development &
process scale up
Release testing &
fill/finish to DP
Ichor
Ichor Medical Systems:DNA Based Antibody Delivery
• Participated in DARPA ADEPT-PROTECT program.• Developed an electroporation based delivery platform for delivery of DNA
encoded monoclonal antibodies (mAb) to provide sustained endogenous expression from a single administration.
• Established collaborations with mAb developers and demonstrated sustained mAb serum levels and protection against viral challenge in non-clinical studies.
Delivery System (TDS-IM)
+DNA
Vector encoding
mAb Intramuscular TriGrid
CandidateAntibody
0 1 2 3 4 5 6
Time (months)
Seru
m m
Ab
Conventional Recombinant mAb Pharmacokinetics
DNA mAb Pharmacokinetics in NHP
LLNL #1
LLNL-PRES-6968941
Simulations using an agent-based model and molecular dynamics will predict successful antibody interactions in the germinal center
Mutation
Proliferation
Affinity selection
Survivalmemory B cells, plasma cells
B cell internalizes antigen with probability determined by MD
helper T-cell
antigen
simulations (1000s ofmutation-specific binding free energy calculated using HPC)
Transport simulated via random hopping process
Bind with a probability determined by MD simulations
Death if B cell fails to internalize antigen after 10 hours
Cell death
Mutations (probability of 10-3 per base pair per division)• prob. of functionally silent mutation = 0.5• prob. of lethal mutation = 0.3• rest are mutations that affect affinity between B cell receptor and antigen
activated naïve B cell
CollaboratorsA. Chakraborty (MIT)M. Karplus (Harvard)
Addresses: Rapidly identify and evolve antibody candidate
NNSA
LLNL-PRES-7251768
Bioprinting Next Generation Tissue System: Instrumented Lymph Nodes
Key Features Needed: - Dynamic Vasculature
(lymphatic and blood vessels)
- Innervation- Highly organized 3D stromal
and lymphoid structure
Printed vascularized tissue = building blocks to creating functional tissue
PARC
MicroJet Particle Drug Delivery • Direct needle-free delivery of
powder payloads to tissue – physical penetration of particles
• Tunable array of collimated jets
– disposable ejector & drug cartridge• Advantages
– High patient throughput, mass population delivery
• Quiet, microjets• No –efield or custom biochem needed
– High dosing with single array scan over large area
– Simple formulations– Precision multi-particle delivery– Tunable dosing
• Showed transdermal delivery of nucleic acid-based dry particles
– Biological response comparable to intradermal injections
High speed jetGas inlet
Skin
Air accelerated post-Venturi nozzle
Drug particlesentrainment inlet
Drug reservoir
Contact: [email protected]
serum SEAP activity
Pulmotect
Boosting the Respiratory Immune System to Provide Rapid, Broad Spectrum Protection
PUL- 042-12 h
% S
urvi
val
Vehicle Only
PUL- 042+12 h
H7N9 Pandemic Influenza H3N2 Influenza
Contact: Brenton Scott, PhD
30
20
10
0
80
70
60
50
40
90
100
PUL- 042-72 h
Vehicle Only
PUL- 042+24 h
PUL- 042+24 h, +72 h
PUL- 042+48 h
% S
urvi
val
➢ Clinical-stage drug➢ Immediate lung activity➢ Long-term stability
Pre- and post-exposure of PUL-042 shows activity against H7N9 and H3N2 viral challenges in mouse models
N=15/group N=15/group
Technology Benefits:➢ Broad spectrum – every pathogen tested to date➢ Host-targeted – reduce pathogen resistance➢ Large scale/ease of manufacturing
[email protected] 713-579-9226
Twist Bioscience
COMBINATORIAL LIBRARIES
• TA2: Evolving Antibodies
• Libraries are:• Rationally designed• Precisely controlled• Large search space
(~10^10 and higher!)• No unintended stop
codons• Bias-free• NGS-verified
• 2-3 design/construct/test:• Improve potency• Improve specificity
• Cost effective• Fast turn-around time
UCSD #1
Hybrid tandem peptide/porous Si
nanoparticle
Tandem peptide nanocomplex
(TPNC)CARG peptide targetingS.aureus infected trachea
Targeting groups: peptides identified by in vivo phage display
Nanoparticles: Porous Si and tandem peptide nanocomplexes
Payload: oligonucleotide or protein
DARPA P3: Nanoparticle Delivery SystemsTeam: Sailor, Bhatia, Ruoslahti, Spinnaker Biosciences
GOAL: Develop means of efficiently delivering nucleic-acid-based protective treatments PROBLEM: Current methods to deliver nucleic acid therapies suffer from inadequate efficacy SOLUTION: Targeted, fusogenic nanoparticle-based nucleic acid delivery vehicles
(1) Build on previous success in treatment of bacterial infections (DARPA ADEPT/PROTECT)(2) Harness peptides that target b cells or macrophages(3) Effectively deliver treatments with safe, proven nanoparticle systems(4) Partner with Spinnaker Biosciences for GMP formulation work
targeting peptides hollow nanoparticles therapeutic payloads
VIRAPUR
• Growth and titration experience with100s of human viruses
• Rapid production of 100s of liters of many high titer viruses for pharma
• Banks of common human and primatecell lines
• Cell selection methodologies for improved virus production
• Protein and nucleic acid based assays for all viruses
• Previous DARPA contract• BSL2 and BSL3
• [email protected]• 858 824-9000
1
• Zika Virus• Influenza viruses• Rhinovirus, Picorna viruses• RSV and Coronaviruses• Vaccinia and Poxviruses
virapur.comSan Diego, CA
• Herpesviruses• Adenoviruses• Parvoviruses• Enteroviruses• Bacteriophage
AbCellera
ABCELLERAABCELLERA
• Therapeutic antibody discovery & development• 14 partnered therapeutic programs since 2015, 100% successful• 5 programs in infectious disease: Ebola, ETEC, Flu, Klebsiella • State-of-the-art capabilities in Human mAb discovery & Immune Profiling• Founded in 2012, 32 employees and rapidly growing
ANTIBODY DISCOVERY PLATFORM • Microfluidic-based single B cell screening• Throughput of >1,000,000 cells per screen• Any species, any tissue• Single cell assay capabilities: cross-reactivity, affinity, cell binding, blocking…• Cells to hundreds of functional antibody sequences in 5 days• High-throughput antibody expression/characterization
ANTIBODY OPTIMIZATION & ENGINEERING• Deep screening of antibody libraries in mammalian cells• Ig-Seq and Bioinformatics • High-throughput affinity ranking (>100,000 mAbs per run)• Early ranking of mAbs in final format – avoid liabilities of display approaches
www.abcellera.com
Scripps
The Scripps Research Institute• Member of DARPAs Autonomous Diagnostics to
Enable Prevention and Therapeutics consortium• High-throughput and rapid isolation and
characterization of mAb during Zika pandemic using whole virus memory B cell isolation technology
Virus expansion to 10^11 PFU
whole virus antigen-specificB cell isolation
Generation of broadly neutralizing and highly potent mAb
Rapid characterization of ~300 mAb
LLNL #2
LLNL-PRES-72517624
Bioprinting Next Generation Tissue System: Instrumented Lymph Nodes
Key Features Needed: - Dynamic Vasculature
(lymphatic and blood vessels)
- Innervation- Highly organized 3D stromal
and lymphoid structure
Printed vascularized tissue = building blocks to creating functional tissue
Vanderbilt
DARPA Pandemic Prevention Platform (P3) Primary Deliverable: Provide a Platform Technology to Provide Pandemic Protection Within 60 Days Following Pathogen Identification
Proposed Platform: Selective TLR3 Agonist to Provide Immediate Immunity Against Any Viral Pathogen within Area of Contagion Risk (Primary Contacts) Prior to Identification and Promote Immune Responses for Antigen Induced Long Term Immunity Against Any Specific Pathogen (Herd Immunity)
Platform Specifics:• Rintatolimod (RNA: Poly I:Poly C12U) proven effective prior to and post exposure to viruses
in all viral classes - DNA, RNA (+ strand), RNA (- strand), and retroviruses in multiple animal models
• Proven efficacious in animal models against select agents (Ebola, SARS-CoV, WEE/VEE)• ~100,000 human doses administered to ~1,000 subjects in multiple open label and blinded
clinical trials including phase 2 and 3 double-blind, placebo-controlled trials • Drug generally well-tolerated with long-term administration with no difference in severe
adverse events between drug and placebo in Phase 2/3 trials• Currently manufactured in 4,000 unit lots (2 units per dose) with at least 4 years of stability
at 40 C (can be stockpiled for immediate availability under common storage conditions)• Regulatory rapid approval potential using FDA animal rule program • Powerful immune driver of mucosal and IM/SC delivery with proven antigen spreading
Duke
• Antigen-specific cell isolation
• Structure/function-based immunogen design
• Broadly neutralizing Abs• Nucleic acid delivery
• GMP/development • CHO and mRNA platforms• Phase I isolation unit• Domestic and International
Clinical Trial sites
• Elucidate immune response to priority pathogens
• Antibody ID & Evolution• Programs in HIV, Flu, TB,
Zika, Dengue, WNV, chlamydia, gonorrhea
• Pathogen Identification• Comprehensive Virology• Mouse, Ferret, Rabbit, NHP• Containment Cell-sorting BSL2/3
ContainmentFacility
HostPathogenInteraction
Vaccine &
Therapeutic Discovery
GMP &
ClinicalTrials
[email protected] - [email protected]
dhvi.duke.edu
Integrated Infectious Disease Research & DevelopmentTo Improve Global Health
Discover
EvolveTranslate
Identify
Synthetic Genomics
| 0C O P Y R I G H T © S Y N T H E T I C G E N O M I C S , I N C.
Combination of synthetic technologies to enable viral rescue and recoveryAnticipated P3 role for Synthetic Genomics
Integrated and rapid manufacturing of RNA-Ab platform once sequence identified
Replicon platform with improved persistent, high gene expression in vivo
● Lead: (1) Synthesis of known Ab genes; (2) Assembly of genes into SGI RNA replicon vector; (3) Synthetically amplify DNA; (4)RNA formulation testing/analysis
● Partners: (1) Grow virus; (2) Affinity mature Ab genes; (3) Conduct in vivo efficacy studies; (4) Manufacture RNA
● SGI technologies can rapidly sequence emerging pathogens
● SGI synthesis technologies allow for assembly of large DNA fragments in days using automation (BioXP)
● Synthetic, purified virus can be rescued in partner labs
● Superior RNA platforms created by experienced team that are capable of elevated expression of reporter genes in vivo (left panel) and multigenic expression of antibodies in vitro (right panel)
Rapid, fully synthetic, self-amplifying RNA expression platforms
0 10 20 30104
105
106
107
108
109
Days
Tota
l Flu
x (p
hoto
ns/s
econ
d)
SGIOriginal
***
*** *
Alphavirus replicon
10/1010/10
10/1010/10
10/1010/10 10/10
10/109/1010/10
8/109/10
3/102/10
BioXp™ 3200
SGI WT DNA100
101
102
103
Ab
expr
essi
on (p
g/ce
ll/da
y)
Alphavirus replicons
Day 5Day 4Day 3Day 2Day 1
Oligos designed and synthesized 24 hours
Ab replicon assembled 12 hours
Ab gene sequence received
Ab gene cassette synthesized and error-corrected 24 hours
DNA amplificationsynthetically 24 hours
DNA template delivered to RNA manufacturer24 hours
RNA manufacture initiated
NSP Cas9 AA…A
NSP Cas9 AA…A
NSP Cas9 AA…A
UCSD #2
Adaptive Laboratory Evolution (ALE)
Harnessing the power of biology to “self-optimize” through mutation and selection
The ALE Process
Starting Strain
Optimized Strain
Adam [email protected]
The Proprietary ALE Technology PlatformLaboratory Automation Process Control Bioinformatics & Databases
>10,000 Mutations from>50 Projects - Identified and
categorized through a bioinformatics pipeline
Clear Plateaus
Sequence & Characterize Here!
• Strict Selection Pressures• Quantitative Data Throughout
• Rapid Mutation Analysis• ALE simulator for Prediction
• Parallel Replicates• Around the clock operation
• Multiple Tunable Parameters
ALE Mutation Database
thrAS357R (AGC→CGC)Y356C (TAC→TGC)
• Previously Found and Context• Structural Implications• Functional Enrichment