ALBERT

Description: Despite the recent advancements in treatment options with the introduction of anti-CD20 monoclonal antibody therapy, approximately 50% of patients with non-Hodgkin's lymphomas (NHL) will not sustain a durable response to standard of care (SOC) treatment. Thus, there remains a continuous need for safer and more effective anti-cancer therapies in this indication. T-cell bispecific antibodies (TCBs) represent a new class of disease targeting agents shown to promote the activation of a patient's own T cells to attack and kill cancer cells. CD20 TCB is a new bispecific antibody with IgG-like pharmacokinetic properties whose unique "2:1" structure leads to increased tumor antigen avidity, T cell activation, and tumor cell killing, as compared to other T cell engaging bispecific antibody molecular formats. The molecule comprises two CD20 binding Fabs (derived from the Type II CD20 IgG1 obinutuzumab), one CD3e binding Fab (fused to one of the CD20 Fabs via a short flexible linker), and an engineered, heterodimeric Fc region with completely abolished binding to FcgRs and C1q. In vitro, CD20 TCB was shown to dose-dependently induce tumor lysis with EC50 values in the range of 0.05 - 3.1 pM. The "2:1"format of CD20 TCB was shown to confer superior potency (up to 10 - 1000x) when compared to CD20 TCBs having the conventional "1:1" IgG-based format (i.e., one binding domain for CD20 and one for CD3). CD20 TCB-mediated tumor lysis resulted in T-cell activation, proliferation and cytokine release with up-regulation of programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) axis upon tumor lysis. CD20 TCB also demonstrated potent ex vivo activity in whole bone marrow aspirate samples of NHL and CLL patients (n=17). Such primary tumor samples preserve the native tumor microenvironment and bear low effector to target cell ratios ranging in this study from 0.02 to 0.8 (average value 0.3). CD20 TCB activity was consistently superior to that of the "1:1" CD20 TCB and demonstrated faster, more profound and more potent B cell depletion with EC50 values ranging from 0.002 to 2.7 nM. In vivo, CD20 TCB displayed potent anti-tumor activity in xenograft models in stem cell humanized mice and induced regression of large, aggressive WSU-DLCL2 lymphoma tumors (0.5 mg/kg, weekly administration). In addition to tumor regression, CD20 TCB treatment led to fast and complete elimination of peripheral blood B cells within 24 h after the first administration (0.05, 0.15 and 0.5 mg/kg, weekly administration) and to a complete elimination of B cells in spleen, bone marrow and lymph nodes after two administrations. B cell depletion was paralleled by transient decrease of T-cell counts in the peripheral blood and by the peak of cytokine release 24 h after the first administration, followed by rapid recovery and return to baseline levels at 72 h post treatment. Tumor growth inhibition mediated by CD20 TCB was accompanied by increase in intra-tumor T-cell infiltration, up-regulation of PD-1 receptor on T cells and PD-L1 in the tumor. Combination studies of CD20 TCB with PD-L1 blocking antibody led to more profound and faster tumor growth inhibition. Taken together, the preclinical data show that CD20 TCB is a novel differentiated CD20-targeting T cell bispecific antibody with promising anti-tumor activity and the ability to modify the tumor microenvironment. CD20 TCB consistently demonstrated superior potency compared to other CD20 TCBs with a conventional "1:1" IgG format. This translated into superior efficacy in vitro, ex-vivo and in vivo, which could not be matched by increasing doses of the "1:1" TCBs. The molecule is now scheduled to start clinical trial by December 2016. Disclosures Bacac: Roche: Employment, Equity Ownership, Patents & Royalties. Umaña:Roche: Employment, Equity Ownership, Patents & Royalties. Herter:Roche: Employment, Patents & Royalties. Colombetti:Roche: Employment. Sam:Roche: Employment. Le Clech:Roche: Employment. Freimoser-Grundschober:Roche: Employment. Richard:Roche: Employment. Nicolini:Roche: Employment. Gerdes:Roche: Employment. Lariviere:Roche: Employment. Neumann:Roche: Employment. Klein:Roche: Employment, Patents & Royalties.

Description: Exchange of groundwater and lake water with typically quite different chemical composition is an important driver for biogeochemical processes at the groundwater-lake interface, which can affect the water quality of lakes. This is of particular relevance in mine lakes where anoxic and slightly acidic groundwater mixes with oxic and acidic lake water (pH〈3). To identify links between groundwater-lake exchange rates and acid neutralization processes in the sediments, exchange rates were quantified and related to pore-water pH, sulfate and iron concentrations as well as sulfate reduction rates within the sediment. Seepage rates measured with seepage meters (-2.5 to 5.8 L m-2 d-1) were in reasonable agreement with rates inverted from modeled chloride profiles (-1.8 to 8.1 L m-2 d-1). Large-scale exchange patterns were defined by the (hydro)geologic setting but superimposed by smaller scale variations caused by variability in sediment texture. Sites characterized by groundwater upwelling (flow into the lake) and sites where flow alternated between upwelling and downwelling were identified. Observed chloride profiles at the alternating sites reflected the transient flow regime. Seepage direction, as well as seepage rate, were found to influence pH, sulfate and iron profiles and the associated sulfate reduction rates. Under alternating conditions proton-consuming processes, for example, sulfate reduction, were slowed. In the uppermost layer of the sediment (max. 5 cm), sulfate reduction rates were significantly higher at upwelling (〉330 nmol g-1 d-1) compared to alternating sites (〈220 nmol g-1 d-1). Although differences in sulfate reduction rates could not be explained solely by different flux rates, they were clearly related to the prevailing groundwater-lake exchange patterns and the associated pH conditions. Our findings strongly suggest that groundwater-lake exchange has significant effects on the biogeochemical processes that are coupled to sulfate reduction such as acidity retention and precipitation of iron sulfides. © 2012 John Wiley & Sons, Ltd.

Description: Im Rahmen dieser Arbeit wurde eine Plattform zur individuellen Ansteuerung einer Vielzahl thermisch aktivierter Mikroventile und aktoren, auf Grundlage eines Phasenüberganges, zum Einsatz in der Mikrofluidik entwickelt. Ventile dienen dazu den Fluidstrom in komplexen mikrofluidischen Systemen, aus Einsatzgebieten wie der Biologie, Chemie oder Biotechnologie, zu manipulieren. Mit steigender Komplexität der Mikrosysteme steigt auch die Anzahl der benötigten, individuell steuerbaren Mikroventile.