A Phase I Dose-Escalation and Pharmacokinetic Study of TrasGEX™ in Patients With Locally Advanced or Metastatic HER-2-positive Cancer
This was a prospective, open label, multicenter study evaluating the safety, tolerability and pharmacokinetics of TrasGEX™ after intravenous administration in patients with HER-2 positive cancers. The effect of TrasGEX™ on the development of anti-drug antibodies and on tumour response was also evaluated.
Phase I study of TrasGEX, a glyco-optimised anti-HER2 monoclonal antibody, in patients with HER2-positive solid tumours.
3区 · 医学
作者: Walter Fiedler ; Herbert Stoeger ; Antonella Perotti ; Guenther Gastl ; Jens Weidmann ; Bruno Dietrich ; Hans Baumeister ; Antje Danielczyk ; Steffen Goletz ; Marc Salzberg ; Sara De Dosso
TrasGEX is a second-generation monoclonal antibody of trastuzumab, glyco-optimised to enhance antibody-dependent cellular cytotoxicity while fully retaining trastuzumab's antigen-binding properties to human epidermal growth factor receptor 2 (HER2). A phase I dose-escalation study was conducted to establish the optimal TrasGEX dose and regimen for phase II studies and to define the safety, pharmacokinetics (PK) and preliminary antitumour activity of TrasGEX.
Patients and methods:
A total of 37 patients with advanced HER2-positive carcinomas and progressive disease received TrasGEX intravenously every 3 weeks until disease progression in doses of 12-720 mg in a three-plus-three dose escalation design, including an expansion cohort at the highest dose.
No dose limiting toxicity was observed, and no maximum tolerated dose was reached. Drug-related adverse events were mainly infusion-related reactions occurring during the first infusion in 51% of patients; all but two were mild-to-moderate. Compared with trastuzumab, the PK parameters were dose dependent, with a mean terminal half-life (t1/2) of 263±99 hours for the 720 mg dose. Clinical benefit in 15 out of 30 (50%) evaluable patients included one ongoing complete response, two partial remissions lasting 16 and 77 weeks and disease stabilisation (SD) in 12 patients lasting a median (range) of 17 (7-26) weeks; three of them had SD of 24, 25 and 26 weeks, respectively.
TrasGEX was safe, well-tolerated and showed antitumour activity in 50% of evaluable patients, all with progressive disease at study entry. Infusions at an interval of 2-3 weeks should achieve clinically relevant trough levels for future studies (NCT01409343).
2015-12-01·Journal of Clinical Pathology3区 · 医学
A glyco-engineered anti-HER2 monoclonal antibody (TrasGEX) induces a long-lasting remission in a patient with HER2 overexpressing metastatic colorectal cancer after failure of all available treatment options
3区 · 医学
作者: Eisner, Florian ; Pichler, Martin ; Goletz, Steffen ; Stoeger, Herbert ; Samonigg, Hellmut
This article discussed about the effect of glyco-engineered anti-HER2 monoclonal antibody (TrasGEX) in a patient with HER2 overexpressing metastatic colorectal cancer after failure of all available treatment options. The author results showed that the patient received 480 mg of TrasGEX i.v. over 4 h and every consecutive cycle on day 21 with an infusion time of 90 min. The results showed that the patient had a decrease of size in lung and liver metastases (sum of the longest diameters, target lesions in the liver and right lower lung lobe reduced from 19.7 to 11.1 cm, target lesion in the right liver lobe from 10 to 5.7 cm) after three cycles. The author concluded that the monoclonal antibody performs in excellent clin. condition with no side effects including cardiotoxicity was occurred.
2014-05-01·Clinical and Vaccine Immunology
Direct neutralization of type III effector translocation by the variable region of a monoclonal antibody to Yersinia pestis LcrV
作者: Ivanov, Maya I. ; Hill, Jim ; Bliska, James B.
Plague is an acute infection caused by the Gram-negative bacterium Yersinia pestis. Antibodies that are protective against plague target LcrV, an essential virulence protein and component of a type III secretion system of Y. pestis. Secreted LcrV localizes to the tips of type III needles on the bacterial surface, and its function is necessary for the translocation of Yersinia outer proteins (Yops) into the cytosol of host cells infected by Y. pestis. Translocated Yops counteract macrophage functions, for example, by inhibiting phagocytosis (YopE) or inducing cytotoxicity (YopJ). Although LcrV is the best-characterized protective antigen of Y. pestis, the mechanism of protection by anti-LcrV antibodies is not fully understood. Antibodies bind to LcrV at needle tips, neutralize Yop translocation, and promote opsonophagocytosis of Y. pestis by macrophages in vitro. However, it is not clear if anti-LcrV antibodies neutralize Yop translocation directly or if they do so indirectly, by promoting opsonophagocytosis. To determine if the protective IgG1 monoclonal antibody (MAb) 7.3 is directly neutralizing, an IgG2a subclass variant, a deglycosylated variant, F(ab')2, and Fab were tested for the ability to inhibit the translocation of Yops into Y. pestis-infected macrophages in vitro. Macrophage cytotoxicity and cellular fractionation assays show that the Fc of MAb 7.3 is not required for the neutralization of YopJ or YopE translocation. In addition, the use of Fc receptor-deficient macrophages, and the use of cytochalasin D to inhibit actin polymerization, confirmed that opsonophagocytosis is not required for MAb 7.3 to neutralize translocation. These data indicate that the binding of the variable region of MAb 7.3 to LcrV is sufficient to directly neutralize Yop translocation.