1. MOVING NOVEL CONCEPTS FROM RESEARCH LABORATORY TO CLINICAL PROOF-OF-PRINCIPLE
BIOPHARMACEUTICAL DEVELOPMENT PROGRAM
BIOLOGICAL RESOURCES BRANCH
DEVELOPMENTAL THERAPEUTICS PROGRAM
NATIONAL CANCER INSTITUTE
FREDERICK, MARYLAND

2. Mission
To produce clinical-grade biopharmaceuticals under current Good Manufacturing Practices (cGMPs) appropriate for Phase I/II (dose-ranging safety and efficacy) and “proof of principle” clinical trials of innovative biopharmaceutical concepts.
To manufacture high-quality laboratory-grade material to support preclinical development for selected innovative projects.

3. Key Assumptions
Concepts are selected for novelty and innovation over derivatives of existing approaches.
Many projects have been previously considered by Pharma and declined due to uncertain technology, regulatory hurdles, or small markets.
Clinical production is focused on meeting requirements for initial proof-of-concept trials, NOT final product requirements for commercial development.
Approximately 1/10 to 1/20 clinical projects may eventually be licensed.
Desired size of program is based on assumptions #1-4 (i.e., 10 to 20+ projects/year to clinic).
Intellectual Property to be retained by Project Originator(s).

4. Where Does the Program Get Its Projects
Peer-Reviewed Extramural Research
Special Competitions
Rapid Access to Intervention Development (RAID) Program
Inter-Institute Program (IIP) for AIDS Projects
National Cooperative Drug Discovery Groups
Intramural NCI Research
Other NIH Programs (NIAID)
Commercial Collaborations With Government
The NCI Selects and Prioritizes Candidate Projects
BDP Provides Feasibility Analyses and Cost Estimates That Are Used in the Selection

5. Capabilities and Resources
Fermentation for Recombinants: 20L, 80L, 100L and 1,000L
Natural Products Fermentation: 30, 300, 3,000 Gallons
Hollow Fiber Mammalian Cell Production (8 Pathways)
Packed Bed Mammalian Cell Production
Process Development and Optimization
Fermentation
Recovery
Refolding
Purification
Assays
Etc.
Clean Room Suite
BL3 Suite QA QC
Management of Required Out-Source Production and Testing
CMC Documentation for IND Submission

6. Major Milestones in a Typical Clinical-Grade Production Project
Pre-Proposal Communications With Potential Investigator-Applicants
Proposal Received by NCI
Initial Review by Staff
Clarify Projects by Posing “Generic Questions” to Applicants
Make Preliminary Feasibility Analysis & Cost Estimates
Identify Any Special Concerns

7. Major Milestones (Continued)
Peer Review by Selection Committee
Committee May Re-Define Project Scope
Staff Re-Examines Feasibility & Cost Estimates
Oversight Committee Review
Staff Present Cost and Feasibility Analysis
Determination of Scope of Project
Re-Evaluation of Progress at Key Milestones

8. Major Milestones (Continued)
Initial Meeting of Staff With Outside Investigator
Initial Project Team Meeting
Define Deliverables
Material Requirements
Formulation
Filling
Special Concerns
Safety
Regulatory
Production
Assays
Special Consultants
Outline Major Milestones
Determine Which Efforts Should Be In-House Versus Out-Source

9. Many Projects Require Substantial Attention at the Outset
Expression System
Ampicillin Selection Pressure
Lab-scale Affinity Purification
Protein Solubility Problems
Low Yield
Errors in Genetic Sequence
Extraneous Genetic Material
Poorly Defined Production System
Inadequate Purification Schemes
Analytical Approaches
Unvalidated or Non-Existent In Vitro Potency Assay
Lack of Key Reagents (e.g., Antibodies to Desired Product)
Poor Biochemical Characterization .

10. Many Projects Require Substantial Attention at the Outset (Continued)
Regulatory and Safety
Raw Material Qualification
Inappropriate Cell Banks
Difficult or Unidentified Toxicology Systems
Failed Vendor Qualification
Other
Intellectual Property Concerns
Delays in Material Transfer Agreements
Contracting Delays

11. Typical Results of One Review Cycle of Project Candidates
20 Projects Submitted for Review
6 Selected
2 – Clinical Development for Phase I Trials
2 – Further Preclinical Development. May be re-reviewed for clinical production.
2 – Production to Support Preclinical Development Only

12. Examples of BDP Projects in Various Stages During 12-Month Interval
Monoclonal Antibodies (19)
Other Mammalian Cell Products (3)
Recombinant Proteins (14)
Natural Products (1)
DNA Vaccines (3)
Genetically-modified Organisms for Vaccines (4) or Gene Therapy (2)
Oligonucleotides (3)
Synthetic Peptides (Many)
Other (1)

13. Summary of Major cGMP Project Milestones During Past 12 Months
Ch-EB6 MoAb (Affinity Purification Reagent) gms
Ch14.18 (Anti-GD2 MoAb for Neuroblastoma Phase III Multi-Center Trial) (2 Lots) ,473 Vials
PCLLUS 3-18MN Peptide Vaccine (HIV) Vials
PCLUS MN Peptide Vaccine (HIV) Vials
LMB-2 (Anti-TAC PE38) Immunotoxin (2 Lots) ,155 Vials
1D12 MoAb (Affinity Purification Reagent) gms
He-Fi 1 MoAb (Clinical) (2 Lots) ,070 Vials
Geldanamycin (Antitumor Antibiotic) (4 Lots) gms

14. Summary of Major cGMP Project Milestones During Past 12 Months (Continued)
HPV-16 E7 (12-20) Peptide Vaccine (HPV) Vials
HPV-16 E7 (86-93) Peptide Vaccine (HPV) Vials
HPV-16 E6 Peptide Vaccine (HPV) Vials
HPV-18 E6 Peptide Vaccine (HPV) Vials
MuB3 MoAb (Clinical) gms
HSV-863 MoAb (Clinical) gms
Patient-Specific Id Vaccines (Lymphoma) Vaccines
Patient-Specific Peptide Vaccines Vaccines

15. Summary of Major cGMP Project Milestones During Past 12 Months (Continued)
Allogeneic Pancreatic Cell Vaccine Patients
c-myb Antisense Oligodeoxynucleotide 6,000 Vials
Bradykinin Antagonist (Preclinical Studies) Grams
EGFR VIII Peptide Vials
Ch 11-1F4 (Anti-Amyloidosis Antibody) GMP Chimeric Clone
Anti-her2/ScFv (Preclinical) mg
rPA (Anthrax Vaccine for Clinical Phase I Trials mg
SEB (Staph Enterotoxin B Vaccine – 2 Lots) 1,647 Vials
7G7 (B6 Anti-IL-2R MoAb [Clinical Bulk]) gms

16. Selected Examples of Projects Leading to Commercial Development
IL-2 DPT (DABL-IL2) R&D supported through National Cooperative Drug Discovery Group mechanism. Licensed for cutaneous T-cell lymphoma.
Anti-EGFR Antibody Manufacture of preclinical material and chimerization of antibody. Currently in licensing trials in head and neck cancer, other malignancies.
Anti-GD2-IL2 Fusion Protein (Melanoma) R&D supported under National Cooperative Drug Discovery Group Mechanism. Manufacture of first clinical lot. Further development underway by company.

17. Selected Examples of Projects Leading to Commercial Development (Continued)
Patient-Specific Id Vaccines for Myeloma & Lymphoma Manufacture of 30+ vaccines/year. Entering controlled trials in lymphoma. CRADAs signed for development for lymphoma and myeloma indications.
Anti-CD22/PE38 Immunotoxin for Lymphoma Manufacture of clinical material for initial trials. Being developed by company.
Anti-CD25/PE38 Immunotoxin for Lymphoma Manufacture of clinical material for initial trials. Licensed by company.
IL7 Cytokine Manufacture of preclinical and clinical material for initial clinical studies. CRADA signed with company.

18. Selected Examples of Projects Leading to Commercial Development (Continued)
Anti-Amyloid Antibody for Amyloidosis. Chimerization of Murine Antibody. Manufacture of preclinical material for evaluation. Clinical production and Cooperative Group Trials to be reviewed by DDG. Project recently licensed by outside Pharmaceutical Company.
Anti-her2 Single Chain Antibody Targeted Liposomes Delivering Chemotherapeutic Agents. Process development and manufacture of initial clinical material underway. Project recently licensed and further development in collaboration with outside Pharmaceutical Company.
Pancreatic Cancer Cellular Vaccines. Manufacture of material for Phase I clinical Trial. Recently licensed by outside Pharmaceutical Company that will help defer costs of material for follow-on Phase II clinical trial.

19. The Idea is Not Enough: Characteristics of Projects With Eventual Commercial Development (With Some Exceptions)
What The Investigator Has Already Done
Defined Candidate Molecule
Comparisons With Similar Products
Characteristics of Molecule Consistent With Pharmaceutical Requirements
Production Adequate
Product Characterization Adequate
Laboratory Standard
In vitro Potency Assay
Stability Studies
Reproducible Model Systems
Early Animal Work Includes Some Toxicology
Scale-up Requirements Practical for Initial Clinical Trials
General: Previous Experience of Investigator

20. Summary
A flexible and adaptive approach to facilitation of clinical proof-of-concept evaluation of promising new biopharmaceutical concepts appears to be a cost-effective approach to increasing the number of innovative clinical development candidates.

21. Dr. Gautam Mitra, Director
ACKNOWLEDGEMENTS
BIOPHARMACEUTICAL DEVELOPMENT PROGRAM
Dr. Gautam Mitra, Director
Development Laboratory
Jianwei Zhu, Head
Bob Testerman
Andy Burnette
Juliet Luo
Vinay Vyas
Yueqing Xie
Joan Tucker
Loren Ward
Nacole Lee
Xiaojin Wu

22. ACKNOWLEDGEMENTS Purification Laboratory Steven Giardina, Head
Aparna Kolhekar
Mary Koleck
Earl Nelson
Scott Jendrek
Tim Ouellette
David Nellis
Fermentation
Jianwei Zhu, Supervisor
Phil Rothchild, Supervisor
Denise Ekstrom
Gary Spencer
John Roach
Ray Rose

23. ACKNOWLEDGEMENTS Cell Culture Beverly Keseling, Head
Clinical Manufacturing
Ed Wang, Head
Ken Huyser
Samir Shaban
BL-3/GMP Unit
Jinhua Lu
Molecular Biology Laboratory
Barry Kobrin, Head
Moria Artlip

24. ACKNOWLEDGEMENTS Quality Assurance Doug Gaum, Head Don Duvall
Ken Sechler
Sheryl Ruppel
Lori Lawson
Sandy Gibson
Quality Control
Dennis Michiel, Head
Bill Utermahlen
Cheryl Mowen
Terry Sumpter
Linda Damuth
Trevor Broadt

25. ACKNOWLEDGEMENTS Bioanalytical Development Laboratory
Gopalan Soman, Head
Abraham Kallarakal
Wanda Hartmann
Xiaoyi Yang
Eying Chen
Hengguang Jiang
Nirmala Saptharishi

26. ACKNOWLEDGEMENTS BIOLOGICAL RESOURCES BRANCH Dr. Karen Muszynski
Dr. Morris Kelsey
Dr. Toby Hecht
Dr. Craig Reynolds
Dr. Rosemarie Aurigemma
Dr. Jason Yovandich

27. Our next speaker is:
Dr. Shanker Gupta
Pharmaceutical Resources Branch
Developmental Therapeutics Program