Getting the glycosylation right: Implications for the biotechnology industry

Glycosylation is the most extensive of all the posttranslational modifications, and has important functions in the secretion, antigenicity and clearance of glycoproteins. In recent years major advances have been made in the cloning of glycosyltransferase enzymes, in understanding the varied biological functions of carbohydrates, and in the accurate analysis of glycoprotein heterogeneity. In this review we discuss the impact of these advances on the choice of a recombinant host cell line, in optimizing cell culture processes, and in choosing the appropriate level of glycosylation analysis for each stage of product development

Phase I Trial of Neoadjuvant Conformal Radiotherapy Plus Sorafenib for Patients with Locally Advanced Soft Tissue Sarcoma of the Extremity

INTRODUCTION: Despite effective local therapy with surgery and radiation (RT), approximately 50% of patients with high grade soft tissue sarcoma (STS) will relapse and die of disease. Since experimental data suggest a significant synergistic effect when anti-angiogenic targeted therapies, such as sorafenib, are combined with RT, we chose to evaluate preoperative combined modality sorafenib and conformal RT in a Phase I/II trial among patients with extremity STS amenable to treatment with curative intent. METHODS: For the Phase I trial, eight patients with intermediate or high grade STS > 5 cm in maximal dimension or low grade STS > 8 cm in maximal dimension received concomitant sorafenib (dose escalation cohort 1:200 bid, cohort 2:200/400 daily) and preoperative RT (50 Gy in 25 fractions). Sorafenib was continued during entire period of RT as tolerated. Surgical resection was completed four to six weeks following completion of neoadjuvant sorafenib/RT. Three sorafenib dose levels were planned. Primary endpoints of the Phase I trial were maximal tolerated dose and dose-limiting toxicity (DLT). RESULTS: Eight patients were enrolled in the Phase I (5 female, median age 44, 3 high grade pleomorphic, 2 myxoid/round cell liposarcoma, 3 other). Median tumor size was 16 cm (range 8–29), and all tumors were located in the lower extremity. Two of 5 patients treated at dose level 2 developed DLT consisting of grade 3 rash not tolerating drug reintroduction. Other grade 3 side effects included anemia, perirectal abscess, and SVT. Radiation toxicity (grade 1 or 2 dermatitis, N=8) and post-surgical complications (3 grade 3 wound complications) were comparable to historical controls and other series of preoperative RT monotherapy. Complete pathologic reponse (≥ 95% tumor necrosis) was observed in 3 patients (38%). CONCLUSION: Neoadjuvant sorafenib in combination with RT is tolerable and appears to demonstrate activity in locally advanced extremity STS. Further study to determine efficacy at dose level 1 is warranted. (NCT#00805727, ClinicalTrials.gov