# Presentation: 068766

## 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**

## 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.

## 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).

## 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

## 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

## 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

## 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

## 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

## 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
- .

## 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

## 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

## 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)

## 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

## 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

## 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

## 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.

## 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.

## 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.

## 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

## 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.

## 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

## 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

## 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

## 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

## ACKNOWLEDGEMENTS

**Bioanalytical Development Laboratory**
- 	Gopalan Soman, Head
- 	Abraham Kallarakal
- 	Wanda Hartmann
- 	Xiaoyi Yang
- 	Eying Chen
- 	Hengguang Jiang
- 	Nirmala Saptharishi

## ACKNOWLEDGEMENTS

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

## Our next speaker is:

**Dr. Shanker Gupta**
**Pharmaceutical Resources Branch**
**Developmental Therapeutics Program**