Pharmacogenetics and pharmacogenomics in oncology therapeutic antibody development.
Pharmacogenetics and pharmacogenomics are keys to the success of personalized medicine, prescribing drugs based on a patient's individual genetic and biological profile. In this review, we will focus on the application of pharmacogenetics and pharmacogenomics in developing monoclonal antibody (MAb) therapeutics in oncology. The significance of pharmacogenomics in MAb therapeutics is highlighted by the association between polymorphisms in Fc receptors and clinical response to anti-CD20 MAb rituximab (Rituxan) or anti-ganglioside GD2 MAb 3F8, as well as the potential link between polymorphisms in HER2 and cardiac toxicity in patients treated with the anti-HER2 MAb trastuzumab (Herceptin). The dependence on gene copy number or expression levels of HER2 and epidermal growth factor receptor (EGFR) for therapeutic efficacy of trastuzumab and cetuximab (Erbitux), respectively, supports the importance of selecting suitable patient populations based on their pharmacogenetic profile. In addition, a better understanding of target mutation status and biological consequences will benefit MAAb development and may guide clinical development and use of these innovative therapeutics. The application of pharmacogenetics and pharmacogenomics in developing MAb therapeutics will be largely dependent on the discovery of novel surrogate biomarkers and identification of disease- and therapeutics-relevant polymorphisms. Challenges and opportunities in biomarker discovery and validation, and in implementing clinical pharmacogenetics and pharmacogenomics in oncology MAb development and clinical practice will also be discussed.
Yan
Li
L
Hematology and Oncology, Clinical Research and Development, Centocor Research & Development, Inc, Wayne, PA 19087, USA. LYan2@cntus.jnj.com
Beckman
Robert A
RA
D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D000912:Antibodies, Neoplasm / Q000737:chemistry; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001709:Biotechnology / Q000379:methods* / Q000639:trends; D004252:DNA Mutational Analysis; D015195:Drug Design; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use; D007167:Immunotherapy / Q000379:methods*; D008495:Medical Oncology / Q000639:trends; D009369:Neoplasms / Q000188:drug therapy*; D010597:Pharmacogenetics / Q000379:methods*; D011110:Polymorphism, Genetic; D000069283:Rituximab; D000068878:Trastuzumab
C419226:3F8 antibody; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D000912:Antibodies, Neoplasm; D000970:Antineoplastic Agents; D007074:Immunoglobulin G; D000069283:Rituximab; D066246:ErbB Receptors; D000068878:Trastuzumab