Purpose: Anti-EGF receptor (EGFR) antibodies and small-molecule tyrosine kinase inhibitors have shown activity in epithelial tumors; however, agents that work by blocking the EGFR growth signal are ineffective when the oncogenic stimulus arises downstream, such as in tumors with KRAS mutations. Antibodies of the IgG 1 subclass can also kill tumor cells directly through antibody-dependent cell-mediated cytotoxicity (ADCC), and the efficacy of this is determined by the interaction of the Fc portion of the target cell-bound antibody and Fc receptors present on immune effector cells.Experimental Design: We report the development of GA201, a novel anti-EGFR monoclonal antibody with enhanced ADCC properties. GA201 was derived by humanization of the rat ICR62 antibody. The Fc region of GA201 was glycoengineered to contain bisected, afucosylated carbohydrates for enhanced binding to FcgRIIIA.Results: In vitro binding of GA201 to EGFR inhibited EGF ligand binding, EGFR/HER2 heterodimerization, downstream signaling, and cell proliferation to a similar extent as cetuximab. However, GA201 exhibited superior binding to both the low-and high-affinity variants of FcgRIIIA. This resulted in significantly enhanced induction of ADCC compared with cetuximab against both KRAS-wild-type and -mutant tumor cells lines. This enhanced ADCC translated into superior in vivo efficacy in a series of mouse xenograft models. Efficacy of GA201 was further increased when administered in combination with chemotherapy (irinotecan).Conclusions: These data suggest that GA201 may be more effective than cetuximab in patients with EGFR-positive solid tumors and may also represent a first-in-class treatment of patients with KRAS-mutated tumors.

International audienceWe have successfully developed an experimental setup that allows collecting in situ X-ray powder diffraction and simultaneously recording full waveform acoustic emissions (AE) at high pressure and temperature (PT) in a DIA multi-anvil device. This setup is a powerful tool for investigating rock embrittlement at high PT due to phase transitions and/or mineral reactions since both reaction progress (and kinetics) and AE triggering can be simultaneously monitored. The dehydration of natural serpentinite samples (antigorite-rich) under deviatoric stress has been investigated by this method since antigorite dehydration is believed to trigger intermediate depth earthquakes through dehydration embrittlement. We performed, beforehand, a series of tests on the cold compression of reference materials with contrasted mechanical behaviors (quartz beads and kaolinite powder). Due to grain crushing, cold compression of quartz gave rise to numerous AE events (several hundreds), which were located within the sample. Cold compression and heating of kaolinite, a ductile material, yielded no AEs, demonstrating that the pressure assembly is noiseless. Unexpectedly, antigorite-rich serpentinite samples produced no detectable AEs in the course of their dehydration under the differential stress imposed by alumina waveguides. The only AEs that were recorded occurred during cold compression. Sample microstructures indicate that conjugate faults inherited from the cold compression stage are activated during or after dehydration of the sample. The "aseismic" slip along these faults could be attributed to the presence of talc (or a talc-like phase) or of fine-grained materials (dehydration reaction products) in the fault gouge. Furthermore, AE triggering can also be influenced by hydraulic diffusivity and the differential stress level on the sample, two parameters that are not controlled in conventional multi-anvil experiments. Our results highlight the fact that coupling between dehydration reactions and seismicity might not be as straightforward as previously thought. In fact, fast reaction kinetics or high reaction extent may inhibit the nucleation of mechanical instabilities through rapid stress relaxation of the solid matrix

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An ultrasonic interferometry high-pressure set-up for elastic wave velocity measurements under simulated Earth's mantle conditions has been developed. A DIA-type multi-anvil apparatus MAX80 permanently located at HASYLAB, Hamburg, Germany for X-ray diffraction (XRD) under in situ condition was equipped for simultaneous ultrasonic measurements. Two of the six anvils were equipped with lithium niobate P-and S-wave transducers of 33.3 MHz natural frequency. The pressure and temperature limits of the high-pressure apparatus were not reduced as a side effect of the modification. The ultrasonic configuration allows all kinds of interferometric measurements with compressional and shear waves. In addition to the classical ultrasonic interferometry the newly developed data transfer function technique (DTF), first described in [J. Phys. Condens. Matter 14 (2002) 11337], is discussed in detail to give the readers the chance to use this valuable and important new method.The results for natural San Carlos olivine up to 3 GPa pressure are compared with published data of several authors. The data for hot-isostatic-pressed anorthite solved discrepancies between published high-pressure and normal-pressure data for polycrystalline anorthite leading to v p ¼ 7.28 km/s, v s ¼ 3.93 km/s at ambient conditions and dv p =dp ¼ 0.027 km/s GPa, dv s =dp ¼ 0.001 km/s GPa. The obtained data sets correspond to published results within the accuracy of the method.As an example for unquenchable phase transitions we measured the elastic wave velocities at the high-pressure clinoenstatite (MgSiO 3 , HCEn) -low-pressure (LCEn) transition at high pressure, high temperature conditions in conjunction with in situ XRD. For ultrasonic interferometry experiments LCEn powder synthesized at ambient pressure was hot-isostatic-pressed at 0.4 GPa and 14008C for 2 h in MAX80 to obtain low-porosity samples. The elastic wave velocities v p and v s of the CEn sample were measured in situ using the classical interferometric technique as well as the recently developed ultrasonic data transfer function (DTF) technique for the elastic wave velocities as a function of pressure at 7008C. To compare the results, v p and v s were measured at 6.7 and 7.5 GPa using both interferometric techniques. The results correspond within the limits of less than 1%.