Andrew Lawrence Frelinger III, Ph.D.

Education:

Ph.D. in Biology, May 1984, Case Western Reserve University, Cleveland, Ohio

Thesis Title: Studies on Oxidized Forms of Parathyroid Hormone

Thesis Advisor: James E. Zull,Ph.D. Professor of Biology

B.S. in Biology, May 1975, San Diego State University, San Diego, CA

Research and Professional Experience:

• Site monitor for clinical trial of RPFA (Rapid Platelet Function Asssay) device required for FDA approval
• Trained clinical research personel in assays and procedures required for clinical trial of RPFA device
• Set up laboratory, established assays, and trained personnel for start-up company developing a novel point-of-care medical device to measure platelet function.
• Significantly shortened device development time through critical insights and actions in converting manual assay to rapid, reliable mechanical assay.
• Generated experimental data and made technical presentations leading to successful strategic partner deals.
• Provided technical response to defend U.S. Patent Office action on enabling patent.
• Full time consultant to Accumetrics from 4/96 to 8/96; currently consulting on part-time basis

• Responsible for project developing and testing novel small diameter tissue engineered vascular graft for peripheral and coronary artery applications
• Oversaw development and execution of assays to assess reproducibility of novel tissue processing method and the purity of the final product and contributed to patent application on same.
• Established in vitro performance characteristics of tissue engineered vascular graft and oversaw pre-clinical testing.
• Contributed protein purification and characterization expertise to other projects.

Received FDA training in Design Control

• Led project team comprised of biologists, chemists, and pharmacologists; Direct supervisory responsibilities for one senior scientist and two research associates
• Developed and validated ELISA, FACS, cell aggregation and cell adhesion assays in support of pre-IND pharmacology
• Evaluated reproducibility of manufacturing, in vivo efficacy, and pharmacokinetics of new drug candidate
• Rapidly re-engineered product to overcome pharmacokinetic limitations
• Established productive contacts and collaborations with outside investigators
• Communicated results in writing and in oral presentations to scientific advisory board and potential strategic partners
• Developed medium throughput in vitro assays to screen for inhibitors of SH2 domain proteins important for signal transduction.

1990-1993 Scientist II, Thrombosis and Hemostasis, Biogen, Inc., Cambridge, Massachusetts.

• Designed screens of natural compounds and phage display libraries for inhibitors of GPIIb-IIIa, thrombin, the thrombin receptor and the endothelin receptor
• Isolated and characterized active components using a variety of biochemical techniques including HPLC, mass spectroscopy and amino acid sequencing
• Rationally designed peptide inhibitors for these targets
• Oversaw modification and characterization of the disintegrin, applaggin, for evaluation as a thrombus imaging agent
• Generated GPIIb-IIIa blocking monoclonal antibody, cloned and sequenced CDR3 region, prepared corresponding peptide and demonstrated inhibitory activity
• Direct supervisory responsibilities for one senior scientist and three research associates; Thrombin Receptor Inhibitor Project Team Leader

• Demonstrated occupancy dependent modulation of epitope expression on a cell surface receptor
• Generated and characterized a panel of monoclonal antibodies directed against ligand-occupied conformers of GPIIb-IIIa
• Showed that ligand induced binding sites (LIBS) mediate functional consequences of ligand binding to the platelet integrin, GPIIb-IIIa.
• Identified and characterized ability of anti-LIBS antibodies to "activate" integrins

• Generated a physical map of monoclonal antibody binding sites on neural cell adhesion molecule (N-CAM)
• Related epitope location to effect on function

• Established HPLC purification procedure for parathyroid hormone (PTH)
• Established chemical identity of oxidized forms of PTH
• Demonstrated differences in biological activity of oxidized forms of PTH

• Isolated and characterized variant forms of calcitonin
• Performed calcitonin and parathyroid hormone RIAs
• Small animal surgery including transplantation of rat medullary thyroid carcinoma

Courses Taught / Invited Speaker

3/8/1995 "Platelet Substitutes" Carolinas Clinical Connection 1995, Myrtle Beach, SC

9/23/1994 "Platelet Substitutes" Transfusion Medicine of the Future Conference, Phoenix, AZ, sponsored by the American Association of Blood Banks

1983-1984 Laboratory in Cellular and Molecular Biology, Case Western Reserve University, Cleveland, OH.

Memberships in Professional Societies

1988-present American Society for Cell Biology

1988-present American Heart Association, Council on Thrombosis

Awards

1990 First Independent Research Support and Transition (FIRST) Award, National Institute of Health

1987-1989 Research Fellowship Award, American Heart Association, California Affiliate

1984-1986 NIH Postdoctoral Traineeship in Neurobiology

1983 CWRU Graduate Alumni Travel Award

1982 American Chemical Society Travel Award

1981 Sigma Xi Research Award

1980-1981 NIH Predoctoral Traineeship

Patents:

1. Ginsberg, M.H., O'Toole, T., Plow, E.F., and Frelinger, A.L. III: Antibodies that bind to a ligand induced binding site on integrin and induce integrin activation. U.S. Patent No. 5,306,620 issued 4/26/1994.
2. Frelinger, A.L. III, Plow, E.F., and Ginsberg, M.H.: Antibodies that bind to a ligand-induced binding site on GPIIIa. U.S. Patent Application No. 07/417,565.
3. Ginsberg, M.H., Frelinger, A.L., and Plow, E.F.: In Vitro methods for determining In Vivo thrombotic events. International Patent Application No. PCT/US 92/03419.

Selected Publications

1. Frelinger, A.L. III, and Hillman, R.S.  Novel Methods for assessiing platelet function.  Am Heart J 1998 135(5 Pt 2 Su):S184-6.
2. Berkowitz, S.D., Frelinger, A.L. III, Hillman, R.. Progress with point-of-care laboratory testing for assessing platelet function. Am Heart J 1998 136(4 Pt 2 Su):S51-65.
3. Frelinger, A.L. III, Alavi-Nassab, A., Wood, S., Cerasoli, F., Iuliucci, J.D., Li, L., Reichert, J., Loiacono, K.A., MacNeil, I.A., Sanford, B., Allen, I.E., Huang, M.M.. (Intr. by B.S. Coller) Specific Detection And Quantification Of Thromboerythrocytes In Biological Samples., Blood (Supplement) 1994.
4. Wencel-Drake, J.D., Frelinger, A.L. III, Dieter, M.G., Lam, S.C. Arg-Gly-Asp-dependent occupancy of GPIIb/IIIa by applaggin: Evidence for internalization and cycling of a platelet integrin. Blood 81:62-9, 1993.
5. Bajt, M.L., Ginsberg, M.H., Frelinger, A.L. III, Berndt, M.C., Loftus, J.C. A spontaneous mutation of integrin alphaIIb-beta3 (platelet glycoprotein IIb-IIIa) helps define a ligand binding site. J Biol Chem 267:3789-94, 1992.
6. Frelinger, A.L. III, Du, X.P., Plow, E.F., Ginsberg, M.H. Monoclonal antibodies to ligand-occupied conformers of integrin alphaIIb-beta3 (glycoprotein IIb-IIIa) alter receptor affinity, specificity, and function. J Biol Chem 266:17106-11, 1991.
7. Loftus, J.C., Plow, E.F., O'Toole, T.E., Glass, A., Frelinger, A.L., and Ginsberg, M.H. A Beta3 integrin mutation abolishes ligand binding and alters divalent cation-dependent conformation. Science 249:915-918, 1990.
8. Du, X.P., Plow, E.F., Frelinger, A.L. III, O'Toole, T.E., Loftus, J.C., Ginsberg, M.H. Ligands "activate" integrin alphaIIb-beta3 (platelet GPIIb-IIIa). Cell 65:409-16, 1991.
9. Frelinger, A.L., and Rutishauser, U.: Topology of NCAM structural and functional determinants. II. Placement of monoclonal antibody epitopes. J. Cell Biol., 103:1729-1737, 1986.