Three evaluable patients were entered at each dose level

Three evaluable patients were entered at each dose level. were dose dependent, with a mean terminal half-life (t1/2) of 26399?hours GNE-049 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 (7C26) weeks; three of them had SD of 24, 25 and 26 weeks, respectively. Conclusion 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 2C3?weeks should achieve clinically relevant trough levels for future studies (“type”:”clinical-trial”,”attrs”:”text”:”NCT01409343″,”term_id”:”NCT01409343″NCT01409343). strong class=”kwd-title” Keywords: phase I, her2, trasgex, glycoengineered monoclonal antibody, solid tumours Key questions What is already known about this subject? Trastuzumab is a mainstay in the treatment of human epidermal growth factor receptor 2 (HER2) overexpressing breast cancer, together with chemotherapy or as monotherapy. In addition to blocking HER2 and counteracting its oncogenic effect, trastuzumab mediates antibody-dependent cellular cytotoxicity (ADCC) primarily in patients with the favourable valine/valine FcRIIIa allotype (20% of the population), less so in patients with the other two allotypes. Studies have shown that defucosylation of the constant fragment C domain of an antibody enhances ADCC to all three FcRIIIa allotypes in vitro and in preclinical models. What does this study adds? TrasGEX is an immunoglobulin G1?glycoengineered monoclonal antibody (mAb) of trastuzumab with the same binding properties to HER2 as trastuzumab but defucosylated to enhance ADCC. TrasGEX was safe and well tolerated by patients with solid tumours and progressive advanced disease, and pharmacokinetic characteristics were similar to those of trastuzumab. Preliminary antitumour activity was observed. Clinical efficacy was independent of the FcRIIIa allotype. How might this impact on clinical practice? TrasGEX and other glycoengineered mAbs, such as tomuzotuximab, may target a wider population replacing the parent antibody in combination therapies. Introduction Trastuzumab, an immunoglobulin G1 (IgG1) humanised monoclonal antibody (mAb) to HER2, is invaluable in the neoadjuvant, adjuvant and palliative treatment of breast cancer overexpressing HER2 in combination with chemotherapy or as monotherapy and is a standard option together with chemotherapy in the treatment of HER2-positive metastatic gastric cancer.1C3 Trastuzumab acts by blocking HER2, a member of the epithelial growth factor receptor family involved in regulating cell growth, survival, differentiation and migration, thus counteracting the oncogenic effect of HER2 overexpression on cancer cells.4 5 GNE-049 Additionally, antibody-dependent cellular cytotoxicity (ADCC) plays a key role in the mechanism of action of trastuzumab. ADCC is dependent on interactions between the constant fragment C (Fc) portion of an antibody and Fc gamma receptors (FcR) on immune effector cells of innate immunity, particularly natural killer?(NK) cells?expressing FcRIIIa6 7 and is affected by FcRIIIa 158 valine (V)/phenylalanine Igf2 (F) genomic polymorphism.8 9 Clinical benefit was observed in 82% of patients with breast cancer receiving trastuzumab plus taxane for metastatic disease GNE-049 that had the favourable genotype FcRIIIa V/V compared with 40% in patients with the V/F or F/F genotype.10 IgG antibody binding to the FcRIIIa on NK cells is affected by the presence of fucose-linked oligosaccharides in the Fc domain. Afucosylated IgG mAbs show improved binding to all FcRIIIa genotypes and enhanced ADCC compared with their fucosylated counterpart.11 12 Preclinical studies showed enhanced ADCC and better antitumour activity in in vivo models of HER2-amplified breast cancer with afucosylated trastuzumab compared with conventional trastuzumab.13 14 TrasGEX is a second-generation antibody of trastuzumab produced in the GlycoExpress system using human glycoengineered production cell lines to give it a fully human glycosylation pattern. In contrast to trastuzumab that is produced on Chinese hamster ovary (CHO) cells, the N-glycans of TrasGEX contain low amounts of fucose that results in a higher binding affinity of TrasGEX to FcRIIIa.