The Division of Monoclonal Antibodies Kathleen A. Clouse, Ph.D., Director CTGTAC - July 26, 2007

Mission of the DMA … to ensure that safe, efficacious, and high quality monoclonal antibody and related products are available to the American people to diagnose, prevent and treat the illnesses that afflict them. … to maintain and retain a diverse, knowledgeable, … to maintain and retain a diverse, knowledgeable, scientifically based and dedicated staff actively scientifically based and dedicated staff actively involved in research and regulatory review involved in research and regulatory review

“Monoclonal antibodies now comprise the majority of recombinant proteins currently in the clinic, with more than 150 products in studies sponsored by companies located worldwide.” Clinical Success of Monoclonal Antibodies Janice Reichert, Tufts University Center for the Study of Drug Development Nature Biotechnology, September 2005

The Division of Monoclonal Antibodies Kathleen Clouse, PhD. Director Patrick Swann, PhD. Deputy Director Laboratory of Cell Biology Kathleen Clouse, PhD, Chief David Frucht, MD Counterbioterrorism: Anthrax Laboratory of Immunobiology Marjorie Shapiro, PhD, Acting Chief Lab of Molec & Dev Immunol Marjorie Shapiro, PhD, Chief Regulatory Science & Policy Branch Patrick Swann, PhD, Chief

Dr. David Frucht Established an independent research program to characterize Established an independent research program to characterize the activity of anthrax lethal toxin in vitro and in vivo the activity of anthrax lethal toxin in vitro and in vivo Reviews products for infectious diseases, including antibodies Reviews products for infectious diseases, including antibodies under consideration for inclusion in the SNS under Emergency under consideration for inclusion in the SNS under Emergency Use Authorization Use Authorization Reviews monoclonal antibodies or related molecules that Reviews monoclonal antibodies or related molecules that function as agonists or antagonists for hematologic indications function as agonists or antagonists for hematologic indications Participates in pre-approval inspections for MoAb products Participates in pre-approval inspections for MoAb products Serves on working groups for guidance document development Serves on working groups for guidance document development (anthrax therapeutics development, drug-drug interactions) (anthrax therapeutics development, drug-drug interactions) Co-Chair, CDER/CBER Inter-Center Biotechnology Counter- Co-Chair, CDER/CBER Inter-Center Biotechnology Counter- Terrorism Working Group Terrorism Working Group Chair, CMC session of the FDA-sponsored workshop on Chair, CMC session of the FDA-sponsored workshop on “Immune Therapies for Anthrax Infection” “Immune Therapies for Anthrax Infection”

Dr. David Frucht Board certified in Internal Medicine & Infectious Diseases Board certified in Internal Medicine & Infectious Diseases Performs weekly clinical rounds at NIH Performs weekly clinical rounds at NIH Serves on Editorial Boards for The Journal of Immunology and Serves on Editorial Boards for The Journal of Immunology and The Journal of Biological Chemistry The Journal of Biological Chemistry Awarded competitive HHS grants (2006 & 2007) and Awarded competitive HHS grants (2006 & 2007) and CBER/FDA grants (2002 & 2003) for CBT research efforts CBER/FDA grants (2002 & 2003) for CBT research efforts Duties as a Commissioned Officer, U.S. Public Health Service Duties as a Commissioned Officer, U.S. Public Health Service - Incident Response Coordination Team, on-call every 5 - Incident Response Coordination Team, on-call every 5 months for deployment (six deployments in 3 years) months for deployment (six deployments in 3 years) - Selected for the Physicians’ Professional Advisory Committee - Selected for the Physicians’ Professional Advisory Committee to the Surgeon General to the Surgeon General

David Frucht, M.D. Research Program Objectives Identify biological markers for the activity of anthrax lethal toxin Identify biological markers for the activity of anthrax lethal toxin (LT) in humans and animal models (LT) in humans and animal models Assess the biological significance of these markers in the Assess the biological significance of these markers in the pathology of toxemia and/or anthrax infection pathology of toxemia and/or anthrax infection Establish the scientific basis for development of more relevant Establish the scientific basis for development of more relevant bioassays to assess product potency bioassays to assess product potency *Important for addressing issues relevant to seeking approval for these products under the “Animal Rule” (i.e., efficacy testing in these products under the “Animal Rule” (i.e., efficacy testing in animal models and not in humans) animal models and not in humans)

David Frucht, M.D. Research Program Milestones Anthrax LT activates murine macrophages, leading to release of Anthrax LT activates murine macrophages, leading to release of IL-1  and IL-18 (J Biol Chem, 2004) - Identification of new IL-1  and IL-18 (J Biol Chem, 2004) - Identification of new biomarkers & strain susceptibility factors biomarkers & strain susceptibility factors Anthrax LT targets human T cells, leading to a blockade in Anthrax LT targets human T cells, leading to a blockade in proliferation and cytokine production (J Immunol, 2005) - A proliferation and cytokine production (J Immunol, 2005) - A pathogenic mechanism and basis for new bioassays pathogenic mechanism and basis for new bioassays Anthrax LT blocks B cell proliferation and immunoglobulin Anthrax LT blocks B cell proliferation and immunoglobulin production (J Immunol, 2006) - A pathogenic mechanism and production (J Immunol, 2006) - A pathogenic mechanism and basis for new bioassay basis for new bioassay