Biochemical Pharmacology Discussion Group and the Biochemical Group of the American Chemical Society (New York Section)
Monoclonal Antibody Therapies: Streamlining Development, Production, Costs
Posted August 31, 2007
A monoclonal antibody (Mab) is a protein produced in the laboratory or in animals that, when injected into a patient, locates and binds to a specific antigen. There are many kinds of Mabs, each one made to find a different substance. Hailed more than three decades ago as "magic bullets" because of their specificity, Mabs are only now coming into their own as treatments for some types of cancer, and other diseases such as rheumatoid arthritis.
On May 22, 2007, monoclonal antibodies were the subject of a meeting of the Academy's Biochemical Pharmacology Discussion Group. Topics discussed included production of Mabs, pharmacokinetics, boosting efficacy, streamlining production, and moving them to the market.
Use the tabs above to view the meeting report and multimedia presentations.
International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)
This organization brings together regulatory authorities of Europe, Japan and the United States and experts from the pharmaceutical industry to set common technical guidelines and requirements for product registration. Documents relevant to monoclonal antibodies include ICH S6: Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals (PDF, 152 KB) and a ICH M3: Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals (PDF, 143 KB).
U.S. Food and Drug Administration
The FDA's guidelines for Mab development: Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Use (PDF, 140 KB).
European Agency for the Evaluation of Medicinal Products (EMEA)
Mab guidelines are available here: Production and Quality Control of Monoclonal Antibodies (Guideline 3AB4a) (PDF, 112 KB).
Adams GP, Schier R, McCall AM, et al. 2001. High affinity restricts the localization and tumor penetration of single-chain fv antibody molecules. Cancer Res. 61: 4750-4755. FULL TEXT
Adams GP, Weiner LM. 2005. Monoclonal antibody therapy of cancer. Nat. Biotechnol. 23: 1147-1157.
Beckman RA, Weiner LM, Davis HM. 2007. Antibody constructs in cancer therapy: protein engineering strategies to improve exposure in solid tumors. Cancer 109: 170-179.
McCall AM, Shahied L, Amoroso AR, et al. 2001. Increasing the affinity for tumor antigen enhances bispecific antibody cytotoxicity. J. Immunol. 166: 6112-6117. FULL TEXT
Shahied LS, Tang Y, Alpaugh RK, et al. 2004. Bispecific minibodies targeting HER2/neu and CD16 exhibit improved tumor lysis when placed in a divalent tumor antigen binding format. J. Bio. Chem. 279: 53907-53914. FULL TEXT
Weiner KM, Adams GP. 2000. New approaches to antibody therapy. Oncogene 19: 6144-6151. FULL TEXT
Weiner LM, Borghaei H. 2006. Targeted therapies in solid tumors: monoclonal antibodies and small molecules. Hum. Antibodies 15: 103-111.
Deng R, Balthasar JP. 2007. Pharmacokinetic/pharmacodynamic modeling of IVIG effects in a murine model of immune thrombocytopenia. J. Pharm. Sci. 96: 1625-1637.
Hansen RJ, Balthasar JP. 2003. Pharmacokinetic/pharmacodynamic modeling of the effects of intravenous immunoglobulin on the disposition of antiplatelet antibodies in a rat model of immune thrombocytopenia. J. Pharm. Sci. 92: 1206-1215.
Hansen RJ, Balthasar JP. 2002. Effects of intravenous immunoglobulin on platelet count and antiplatelet antibody disposition in a rat model of immune thrombocytopenia. Blood 100: 2087-2093. FULL TEXT
Hansen RJ, Balthasar JP. 2002. Intravenous immunoglobulin mediates an increase in anti-platelet antibody clearance via the FcRn receptor. Thromb Haemost. 88: 898-899.
Lobo ED, Hansen RJ, Balthasar JP. 2004. Antibody pharmacokinetics and pharmacodynamics. J. Pharm. Sci. 93: 2645-2668.
Ober RJ, Radu CG, Ghetie V, Ward ES. 2001. Differences in promiscuity for antibody–FcRn interactions across species: implications for therapeutic antibodies. Int. Immunol. 13: 1551-1559. FULL TEXT
Prabhat P, Gan Z, Chao J, et al. 2007. Elucidation of intracellular recycling pathways leading to exocytosis of the Fc receptor, FcRn, by using multifocal plane microscopy. Proc. Natl. Acad. Sci. USA 104: 5889-5894.
Vaccaro C, Bawdon R, Wanjie S, et al. 2006. Divergent activities of an engineered antibody in murine and human systems have implications for therapeutic antibodies. Proc. Natl. Acad. Sci. USA 103: 18709-18714. FULL TEXT
Vaccaro C, Zhou J, Ober RJ, Ward ES. 2005. Engineering the Fc region of immunoglobulin G to modulate in vivo antibody levels. Nat. Biotechnol. 23: 1283-1288.
T. Shantha Raju
Raju TS, Scallon B. 2007. Fc glycans terminated with N-acetylglucosamine residues increase antibody resistance to papain. Biotechnol. Prog. [in press].
Raju TS, Scallon B. 2006. Glycosylation in the Fc domain of IgG increases resistance to proteolytic cleavage by papain. Biochem. Biophys. Res. Commun. 341: 797-803.
Scallon BJ, Tam SH, McCarthy SG, et al. 2007. Higher levels of sialylated Fc glycans in immunoglobulin G molecules can adversely impact functionality. Mol. Immunol. 44: 1524-1534.
Keith Canada, PhD
Keith Canada is a senior scientist in the Biologics and Biomolecular Sciences division of Boehringer Ingelheim Pharmaceuticals.
Louis M. Weiner, MD
Louis Weiner is chairman of the Department of Medical Oncology and vice president of translational research at the Fox Chase Cancer Center. His work focuses on conducting translational research employing targeted therapy of cancer by antibody-based proteins. He serves on numerous National Cancer Institute review panels, including the Translational Research Working Group (TRWG), the Cancer Immunopathology and Immunotherapy (CII) study section, and the Rapid Access to Intervention Development (RAID) program oversight committee. Weiner completed his medical education at the Mount Sinai School of Medicine and has held fellowships at the New England Medical Center Hospital at Tufts University School of Medicine.
Joseph P. Balthasar, PhD
Joseph Balthasar is an associate professor of pharmaceutical sciences at the University of Buffalo. He completed his PhD in pharmaceutics at the State University of New York at Buffalo. His research focuses on the application of pharmacokinetic and pharmacodynamic analyses to design new treatments for ovarian cancer and for autoimmune diseases.
E. Sally Ward, PhD
Sally Ward is the Paul and Betty Meek–FINA Professor in Molecular Immunology at the University of Texas Southwestern Medical Center. Her laboratory's primary interest is in investigating how FcRn functions as an IgG transporter to regulate IgG levels throughout the body. She is also working to develop engineered antibodies that are altered in their binding properties for FcRn and, as such, can modulate FcRn function. Ward completed her undergraduate and doctoral degrees at the University of Cambridge and held two fellowships there before migrating to the United States.
T. Shantha Raju, PhD
Shantha Raju is a research fellow at Centocor R&D, a biotechnology company owned by Johnson & Johnson.
Kevin Bailey, PhD
Kevin Bailey is vice president of preclinical manufacturing and process development at Regeneron Pharmaceuticals.
Gordon Moore, PhD
Gordon Moore is senior director of cell biology at Centocor Pharmaceutical Development.
Patrick Garidel, PhD
Patrical Garidel is head of pharmaceutical basic development at Boehringer Ingelheim Pharma GmbH & Co. KG, based in Biberach an der Riss, Germany.
Paul Andrews, PhD
Paul Andrews is vice president of research and development at Patrys, Ltd. His duties include designing, implementing, and managing nonclinical safety assessment programs to support clinical development of Patrys' IgM monoclonal antibodies; preparing regulatory submissions; participating in IND-candidate selection; formulating early clinical development plans; and participating in partnering efforts. Prior to joining Patrys, he was assistant vice president of toxicology at ImClone Systems, where he supervised the nonclinical development of monoclonal antibody therapeutics and the nonclinical bioanalytical laboratory. He has also held positions at Aton Pharma and Cato Research, and worked as pharmacology team leader at the U.S. Food and Drug Administration's Division of Oncology Drug Products. He earned his PhD in medicinal chemistry from the University of Maryland at Baltimore.