The biology of the human epidermal growth factor (EGF) receptor-2 (HER2) has been reviewed numerous times and provides an excellent example for developing a targeted cancer therapeutic. Herceptin, the FDA-approved therapeutic monoclonal antibody against HER2, has been used to treat over 150,000 women with breast cancer. However, the developmental history of Herceptin, the key events within the program that created pivotal decision points, and the reasons why decisions were made to pursue the monoclonal antibody approach have never been adequately described. The history of Herceptin is reviewed in a way which allows the experience to be shared for the purposes of understanding the drug discovery and development process. It is the objective of this review to describe the pivotal events and explain why critical decisions were made that resulted in the first therapeutic to successfully target tyrosine kinases in cancer. New approaches and future prospects for therapeutics targeting the HER family are also discussed.

The emergence of diseases associated with telomere dysfunction, including AIDS, aplastic anemia and pulmonary fibrosis, has bolstered interest in telomerase activators. We report identification of a new small molecule activator, GRN510, with activity ex vivo and in vivo. Using a novel mouse model, we tested the potential of GRN510 to limit fibrosis induced by bleomycin in mTERT heterozygous mice. Treatment with GRN510 at 10 mg/kg/day activated telomerase 2–4 fold both in hematopoietic progenitors ex vivo and in bone marrow and lung tissue in vivo, respectively. Telomerase activation was countered by co-treatment with Imetelstat (GRN163L), a potent telomerase inhibitor. In this model of bleomycin-induced fibrosis, treatment with GRN510 suppressed the development of fibrosis and accumulation of senescent cells in the lung via a mechanism dependent upon telomerase activation. Treatment of small airway epithelial cells (SAEC) or lung fibroblasts ex vivo with GRN510 revealed telomerase activating and replicative lifespan promoting effects only in the SAEC, suggesting that the mechanism accounting for the protective effects of GRN510 against induced lung fibrosis involves specific types of lung cells. Together, these results support the use of small molecule activators of telomerase in therapies to treat idiopathic pulmonary fibrosis.

Gene therapy has entered a new era where numerous therapies for severe and rare diseases are generating robust and compelling clinical results. The rapid improvements in gene therapies over the past few years can be attributed to better scientific understanding of the critical quality attributes that contribute to a safe and efficacious product, as well as a better understanding of the manufacturing processes that are required to yield consistent products, which routinely meet the quality standards required for clinical studies. Of particular concern is the need for an effective, quality control (QC)-compatible, and versatile test method for the quantification of empty and full capsids in recombinant adeno-associated virus (rAAV) samples from multiple serotypes. In that regard, we describe the development of a QC-compatible anion-exchange chromatography method consisting of a modular discontinuous gradient to achieve full baseline peak separation and quantification of empty and full AAV capsids. Using an rAAV6 vector, our assay was shown to be precise, linear, robust, and accurate-correlating well with orthogonal methods such as analytical ultracentrifugation (AUC) and cryogenic transmission electron microscopy (Cryo-TEM). Additionally, we demonstrate the versatility of our approach by adapting the method to separate and quantify empty/full capsids in samples from several rAAV serotypes.

Background: Telomerase maintains telomere length (TL) of dividing cells, and is essential for cell immortalization. Telomerase is upregulated in tumors, particularly in cancer progenitor cells. Imetelstat (GRN163L), the first targeted telomerase inhibitor in clinical trials, is a 13-mer lipidated oligonucleotide that binds to the template RNA strand of telomerase. With weekly dosing, thrombocytopenia was dose limiting and MTD was 4.8 mg/kg. To increase drug exposure and maintain tolerability, we tested an intermittent dosing schedule of imetelstat. Methods: Patients (pts) with advanced solid cancers were given imetelstat as a single agent by 2 hr. i.v. infusions on D1 and D8 of 21-Day cycles (Cy), starting at 4.8 mg/kg. A 3+3 dose escalation was used. Pre-treatment granulocyte TL (PMN TL), a surrogate of hematopoietic progenitor TL, was measured by Flow-FISH. Results: 31 pts have been treated, with 4 currently on study. Mean number of prior cytotoxic regimens reported for 26 pts was 3.6 and 16 pts had prior irradiation. Dose escalation proceeded to 11.7 mg/kg, which was judged to be in excess of the MTD due to cytopenias. Three pts had been previously treated with 9.4 mg/kg without DLT, and the 9.4 mg/kg cohort was subsequently expanded to 12 pts, maintaining q21 D dosing. To date, severe myelosuppression has been observed in only 1 pt, and all 12 completed Cy 1. Three pts had doses held in Cy 2 for thrombocytopenia. Eight pts discontinued treatment after completing 1 to 4 Cy, 6 for PD, 1 for a hypersensitivity reaction and 1 for an unrelated SAE. Four pts are currently on treatment and have completed 2 to 3 Cy. Hypersensitivity reactions were observed in 5 of 31 pts dosed to date and were associated with biochemical evidence of complement activation; one was managed with secondary prophylaxis with steroids and antihistamines, and routine primary prophylaxis was subsequently instituted for all patients. Transient (<24hr) prolongation of aPTT occurs without clinical sequelae. Other AEs were non-specific, mild to moderate and of dubious causality. Mean ± SD (N) imetelstat AUC-inf from pts treated with 7.5, 9.4 and 11.7 mg/kg were 1036 ± 359 (3), 1219 ± 109 (2) and 1408 ± 812 (6), respectively. By comparison, antitumor effects were noted in xenograft models with AUC-inf of 819. Preliminary analysis of pre- and post-treatment hair follicle samples for pharmacodynamic activity suggests a trend for telomerase inhibition. As previously noted*, thrombocytopenia correlated with short baseline PMN TL among 17 pts. Conclusions: Intermittent dosing of imetelstat at 9.4 mg/kg was well tolerated for multiple cycles. Drug exposures were in a range associated with antitumor activity in preclinical models and preliminary evidence of a pharmacodynamic effect has been observed. Hematologic toxicity is doselimiting, and may be mechanism-based. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C169.