MOVING NOVEL CONCEPTS FROM RESEARCH LABORATORY TO CLINICAL PROOF-OF-PRINCIPLE

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) 6 gms • Ch14.18 (Anti-GD2 MoAb for Neuroblastoma Phase III Multi-Center Trial) (2 Lots) 1,473 Vials • PCLLUS 3-18MN Peptide Vaccine (HIV) 145 Vials • PCLUS 6.1-18MN Peptide Vaccine (HIV) 145 Vials • LMB-2 (Anti-TAC PE38) Immunotoxin (2 Lots) 3,155 Vials • 1D12 MoAb (Affinity Purification Reagent) 15 gms • He-Fi 1 MoAb (Clinical) (2 Lots) 1,070 Vials • Geldanamycin (Antitumor Antibiotic) (4 Lots) 700 gms

14. Summary of Major cGMP Project Milestones During Past 12 Months (Continued) • HPV-16 E7 (12-20) Peptide Vaccine (HPV) 711 Vials • HPV-16 E7 (86-93) Peptide Vaccine (HPV) 740 Vials • HPV-16 E6 Peptide Vaccine (HPV) 180 Vials • HPV-18 E6 Peptide Vaccine (HPV) 954 Vials • MuB3 MoAb (Clinical) 49 gms • HSV-863 MoAb (Clinical) 32 gms • Patient-Specific Id Vaccines (Lymphoma) 18 Vaccines • Patient-Specific Peptide Vaccines 6 Vaccines

15. Summary of Major cGMP Project Milestones During Past 12 Months (Continued) • Allogeneic Pancreatic Cell Vaccine 11 Patients • c-myb Antisense Oligodeoxynucleotide 6,000 Vials • Bradykinin Antagonist (Preclinical Studies) 29 Grams • EGFR VIII Peptide 500 Vials • Ch 11-1F4 (Anti-Amyloidosis Antibody) GMP Chimeric Clone • Anti-her2/ScFv (Preclinical) 500 mg • rPA (Anthrax Vaccine for Clinical Phase I Trials 400 mg • SEB (Staph Enterotoxin B Vaccine – 2 Lots) 1,647 Vials • 7G7 (B6 Anti-IL-2R MoAb [Clinical Bulk]) 7 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. 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