Reimagining Protein Manufacturing (RPM)

Transcription

1 Reimagining Protein Manufacturing (RPM) Amy Jenkins, Ph.D. Biological Technologies Office, Program Manager Briefing Prepared for RPM Proposer s Day August 5, 2021 DISTRIBUTION STATEMENT A. Approved for public release; distribution is unlimited. 1

2 DARPA Introductions: Government team Amy Jenkins DARPA Biological Technologies Office, Program Manager Kerri Dugan DARPA Biological Technologies Office, Director Shane Lomelin DARPA Contracts Management Office Stephanie A. McElhinny ARO, Contracting Officers Representative DISTRIBUTION STATEMENT A. Approved for public release; distribution is unlimited. 2

3 Guest Speakers Christopher Houchens BARDA, Director Division of CBRN Countermeasures Matthew Hepburn HHS DoD Countermeasures Acceleration Group, Director of COVID Vaccine Development DISTRIBUTION STATEMENT A. Approved for public release; distribution is unlimited. 3

4 RPM SETA Support Melissa St. Amand DARPA SETA Technical/RPM Lead Kathryn Wildt DARPA SETA Technical Audrey Glynn DARPA SETA Technical Shawn Rich DARPA SETA Business/Financial John Slawinski DARPA SETA Security David Swan DARPA SETA BAA Coordinator DISTRIBUTION STATEMENT A. Approved for public release; distribution is unlimited. 4

5 Presentation Outline Vision Rationale Structure Timeline DISTRIBUTION STATEMENT A. Approved for public release; distribution is unlimited. 5

6 Vision for Reimagining Protein Manufacturing (RPM) DoD Problem: DoD lacks a distributed solution for producing complex biological materials critical to medical readiness and supply chain maintenance Complex Proteins Today s Manufacturing Centralized, Static, Heavily linked to supply chain Tomorrow s Manufacturing Distributed, On-Demand, Removed from supply chain Therapeutics Vaccine subunits Raw material enzymes Vision: Establish the foundational technologies needed for fully distributed, on-demand manufacturing of biologics-based medical countermeasures (MCM) and their associated raw materials DISTRIBUTION STATEMENT A. Approved for public release; distribution is unlimited. 6

7 One Year of the COVID-19 Pandemic Jan 31 EUA declares global health emergency Jun 1 AbCellera/Eli Lilly mab enters Ph 1 Nov 9 FDA grants EUA to AbCellera/Eli Lilly mab for COVID treatment 101,459 US deaths 129,253 US deaths (230,712 total US deaths) Base Graphic: Washington Post DISTRIBUTION STATEMENT A. Approved for public release; distribution is unlimited. 7

8 DoD Relevance Military needs agile technology to increase on-demand MCM production Emergencies are distributed but typical response is centralized Mil-Mil Medical Operations Maintain stability during both peace and conflict: Syria Operation Warp Speed United States M infected, 500K dead from COVID 19 Operation United Assistance West Africa >4K personnel, 101 st Airborne operational lead Operation Tomodachi Japan K personnel, 24 ships, 89 aircraft NOW systems require specialized raw materials - manufacturing enzymes Decontamination Broad classes of MCMs rely on proteins: Antibodies Nucleic acids Clotting factors Diagnostic components DISTRIBUTION STATEMENT A. Approved for public release; distribution is unlimited. 8

9 Distributed Protein Manufacturing Will Allow for On-Demand MCM Production Enabling capabilities are required for fully distributed protein manufacturing Engineering Challenges Biochemistry Challenges Automated process control with realtime release Production ready within 24 hours Resilient upstream supply chain; cheap, CONUSsourced materials Worldwide Distributed Protein Manufacturing High yield/high purity (>500 doses per week) RPM addresses the biochemistry challenges Distributed manufacturing footprint Protein modifications (different types, multiple sites) DISTRIBUTION STATEMENT A. Approved for public release; distribution is unlimited. 9

10 RPM Technical Areas Establish foundational technologies needed for fully distributed, on-demand manufacturing of protein-based MCMs and associated raw materials TA1: Production Yield and Time TA2: Protein Modifications Antibody MCM Martin et al ACS Synthetic Biology van Erp et al Frontiers in Immunology. DISTRIBUTION STATEMENT A. Approved for public release; distribution is unlimited. 10

11 Pre-Program Program Phases, Demonstrations, and Metrics Phase I - Proof of Concept 26 months Phase II - Prototype 24 months FY21 FY22 FY23 FY24 FY25 FY26 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Timeline TA1 Metrics for Capability Demonstration TA2 Metrics for Capability Demonstration IV&V Capability Demonstration 1 11 months Produce: 1 performer-selected protein 1 > 5 kda Reactor > 1mL Purity > 80% Lead time < 14 days Yield see slide 14 Protein modifications O-linked Glycans Protein Quality Characteristics Equivalent to relevant SOA metric 3 Capability Demonstration 2 22 months Produce: 2 performer-selected proteins 1 > 30 kda Reactor > 1mL Purity > 85% Lead time < 5 days Yield see slide 14 Protein modifications O-linked & N-linked glycans > 1 site (same or different modification) Protein Quality Characteristics Equivalent to relevant SOA metric 3 Capability Demonstration 3 38 months Produce: 3 program-selected proteins 1 > 150 kda 2 Reactor <10L Purity > 90% Lead time < 3-5 days Yield see slide 14 Protein modifications O-linked & N-linked glycans > 2 sites (same or different modification) Protein Quality Characteristics Better than relevant SOA metric 3 Function, stability, and composition of the proteins produced during each capability demonstration will be assessed through a series of field recognized analytical techniques Performance by the end of 50 months: Production at a rate of 500 doses/week Capability Demonstration 4 48 months Produce: 3 program-selected proteins 1 > 150 kda 2 Reactor < 10L Purity > 95% Lead time ~24 hours Yield see slide 14 Protein modifications O-linked & N-linked glycans 2 additional types of PTM at > 3 sites Protein Quality Characteristics Better than relevant SOA metric 3 TC 1 Proteins will be chosen from five classes (vaccine subunits, monoclonal antibodies, clotting factors, raw material nucleic acid BAA PD SS Award KO production enzymes, and other therapeutic proteins) each chosen protein must come from a different class Program 2 At least one protein selected for the capability demonstrations 3 and 4 will be > 150 kda Completion 3 See Slide 13 DISTRIBUTION STATEMENT A. Approved for public release; distribution is unlimited. 11

12 Capability Demonstrations 10 L Produce and Purify Protein (1 week) Ship samples to IV&V team IV&V team analyzes protein Obtain DNA/RNA template Prepare Reaction (1 Day) Ship raw materials for reaction to IV&V team IV&V team produces, purifies, and analyzes protein DISTRIBUTION STATEMENT A. Approved for public release; distribution is unlimited. 12

13 Protein Quality Characteristics Protein Quality Characteristic Composition Purity Target binding/activity Glycosylation profile Potency/in vivo efficacy Bioburden Endotoxin Example Quantitative Metric > 95% target product < 5% dimers, aggregates, fragments % relative potency < 10% variance between batches Efficacy comparable to SOA production method 0 CFU/mL < 0.5 EU/mL Performers must show SOA equivalence to appropriate metrics during capability demonstrations During capability demonstrations 3 and 4, performers must select at least one characteristic upon which to improve DISTRIBUTION STATEMENT A. Approved for public release; distribution is unlimited. 13

14 Target Proteins and associated yield metrics Product Type Capability Demonstration 1 Capability Demonstration 2 Capability Demonstration 3 Capability Demonstration 4 Antibodies 3 g/week (10 doses per week) 15 g/week (50 doses per week) 75 g/week (250 doses per week) 150 g/week (500 doses per week) Subunit Vaccine 2 mg/week (100 doses per week) 11 mg/week (500 doses per week) 55 mg/week (2500 doses per week) 110 mg/week (5000 doses per week) Production Enzymes Clotting Factors 100 mg per week 500 mg per week 2.5 g per week 5 g per week 50 mg/week (10 doses per week) 250 mg/week (50 doses per week) 750 mg/week (250 doses per week) 2.5 g per week (500 doses per week) Therapeutic proteins (ex. scfv, nanobodies, GCSF) Performer determined metric that aligns with above prescribed metrics Performer determined metric that aligns with above prescribed metrics Performer determined metric that aligns with above prescribed metrics Performer determined metric that aligns with above prescribed metrics DISTRIBUTION STATEMENT A. Approved for public release; distribution is unlimited. 14

15 Final Checklist of Requirements TA1 approach (see BAA section for detailed list) TA2 approach (see BAA section for detailed list) Proteins proposed for CD1 & CD2 Performers must select one protein > 5 kda for year 1 and 2 proteins > 30 kda for year 2 Each protein must represent a different class Proteins should require O-linked Glycosylation and/or N-Linked Glycosylation for function Yield metrics for CD1 & CD2 proteins and rationale (if those laid out in the BAA Table 3 are not appropriate) Protein Quality Characteristics for CD1 & CD2 proteins and rationale (if those laid out in BAA table 6 are not appropriate) Potency/in vivo efficacy metric for CD1 and CD2 proteins and rationale Capabilities for purifying each protein class (see BAA section for list of protein classes) Capabilities for assessing quality (see BAA table 6 for list of quality attributes of interest) DISTRIBUTION STATEMENT A. Approved for public release; distribution is unlimited. 15

16 DOD Relevance of Target Proteins In-Scope Out-of-Scope Vaccines for disease prevention Monoclonal antibodies for pandemic response Clotting factors for trauma response Manufacturing enzymes for nucleic acid production Treatments for radiological and chemical threats Cancer treatments Arthritis therapies Cardiovascular medications Alzheimer s treatments... Cholera Vaccine VRC114 Antibody for Ebola Treatment Clotting Factor X T7 Polymerase G-CSF DISTRIBUTION STATEMENT A. Approved for public release; distribution is unlimited. 16

17 DISTRIBUTION STATEMENT A. Approved for public release; distribution is unlimited. 17