Clofarabine tyrosine kinase activity of HER could oncogenically transform

dies were shown to effectively inhibit the signaling activity of EGFR and, more important, resulted in significant inhibition of tumor growth and survival. Hybritech, Inc. licensed one of Mendelsohn’s mouse monoclonal antibodies (mAb), mAb 5, from the University of California and embarked on scale-up production, formulation, and preclinical Clofarabine pharmacology. 4 A phase I clinical trial at Memorial Sloan-Kettering Cancer Center showed that mAb 5 was safe and well tolerated in humans, showed good pharmacokinetic properties, and selec- tively localized at tumor sites.

All of the patients, however, developed human anti-mouse antibodies (HAMA). To  Rivaroxaban overcome the HAMA reaction to mAb 5, the National Cancer Institute Biologics Decision Network Committee issued a contract for a research organization to develop a humanized human-mouse chimeric version of mAb 5, which became known as C5. Though Hybritech was involved in the initial commercialization effort of Mendelsohn’s antibody, the rights to C5 were returned to the University of California following Hybritech’s acquisition by Eli Lilly. In 993, ImClone obtained a license from the University of California for the clinical development and commercialization of C5. ImClone scaled up manufacture of C5, which became known as cetux- imab (Erbitux), and sponsored clinical trials with aca- demic collaborators to evaluate the efficacy of cetux- imab in different types of cancer patients. The results from a clinical trial on CRC patients with academic collaborators led to US Food and Drug Administra- tion approval in 004 for cetuximab in combination DOI:0.00/MSJ The background science and rationale for EGFR as a target for cancer drug discovery and the key tool reagent, mAb 5, which was developed into a clinical therapeutic, were the result of the efforts by Mendelsohn and many other academic investigators. Manufacture and clinical development were mainly driven by industry efforts, initially by Hybritech and then by ImClone, through sponsorship of clinical tri- als with academic groups.

Though cetuximab is an approved and marketed drug, not all treated patients benefit. This has led to efforts to identify biomark- ers and accompanying diagnostic tests to identify the patients most likely to benefit from treatment with cetuximab. EGFR expression has been extensively studied, but has not been shown to be particu- larly useful as a predictive supplier Itraconazole biomarker. 6 The KRAS mutation status appears to predict a poor response to cetuximab in CRC cancer patients, but may not be predictive in NSCLC patients. 7 This suggests that mechanistically, KRAS mutations alone may not pre- clude cetuximab from being effective, but that other tumor-type-specific factors are involved and need to be considered in developing future diagnostic biomarkers.

These academic observations have major implications for the use and commercialization of cetuximab, therefore an area for mutual academic and industry study. Cetuximab is price Itraconazole currently marketed by Bristol-Myers Squibb/ImClone and approved for certain types of CRC and SCCHN patients in specified single-agent and combination modalities. DEVELOPMENT OF HERCEPTIN The oncogenic properties of the neu gene in rats were first described by Robert Weinberg’s labora- tory at the Massachusetts Institute of Technology. 8 Several groups, including scientists at Genentech, identified the human homolog of neu, HER . 9 Subse- quent studies by other academic investigators showed that the protein tyrosine kinase activity of HER could oncogenically transform  infectious normal cells, either through activating mutations or overexpression of the wild-type protein. ,9 Drs Slamon and McGuire in academia and Dr Ulrich in industry at Genentech noted the clinical relevance of HER in breast cancer 9 and embarked on an oncology collaboration target- ing HER. Scientists at Genentech developed mAbs against human the extracellular domain of HER and were able to show that some of the mAbs were potent growth inhibitors of HER-expressing

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