On-target restoration of a split T cell-engaging antibody for precision immunotherapy

T cell-engaging immunotherapies are changing the landscape of current cancer care. However, suitable target antigens are scarce, restricting these strategies to very few tumor types. Here, we report on a T cell-engaging antibody derivative that comes in two complementary halves and addresses antigen combinations instead of single molecules. Each half, now coined hemibody, contains an antigen-specific single-chain variable fragment (scFv) fused to either the variable light (V-L) or variable heavy (V-H) chain domain of an anti-CD3 antibody. When the two hemibodies simultaneously bind their respective antigens on a single cell, they align and reconstitute the original CD3-binding site to engage T cells. Employing preclinical models for aggressive leukemia and breast cancer, we show that by the combinatorial nature of this approach, T lymphocytes exclusively eliminate dual antigen-positive cells while sparing single positive bystanders. This allows for precision targeting of cancers not amenable to current immunotherapies

Contrasting disease patterns in seropositive and seronegative neuromyelitis optica: A multicentre study of 175 patients

BACKGROUND: The diagnostic and pathophysiological relevance of antibodies to aquaporin-4 (AQP4-Ab) in patients with neuromyelitis optica spectrum disorders (NMOSD) has been intensively studied. However, little is known so far about the clinical impact of AQP4-Ab seropositivity. OBJECTIVE: To analyse systematically the clinical and paraclinical features associated with NMO spectrum disorders in Caucasians in a stratified fashion according to the patients' AQP4-Ab serostatus. METHODS: Retrospective study of 175 Caucasian patients (AQP4-Ab positive in 78.3%). RESULTS: Seropositive patients were found to be predominantly female (p 1 myelitis attacks in the first year were identified as possible predictors of a worse outcome. CONCLUSION: This study provides an overview of the clinical and paraclinical features of NMOSD in Caucasians and demonstrates a number of distinct disease characteristics in seropositive and seronegative patients

Design guidelines for the separation of components to combine the potentials of additive and conventional manufacturing processes

Additive manufacturing offers great potential in the geometric design of components. However, there are also restrictions that must be taken into account. These have already been studied and described in the literature. In order to improve the design of components for additive manufacturing, the restrictions are documented in the form of design guidelines and made available to the designer. The design guidelines show a geometry that is less suitable for additive manufacturing and what adjustments must be made to this geometry to enable or improve manufacturing. However, such an adaptation of the geometry is not always possible. This paper therefore extends existing design guidelines in order to specifically aim for the combined manufacturing of the components with different manufacturing processes and to use this as a means to comply with the restrictions of additive manufacturing. In this way, the potential of additive manufacturing is combined with the potential of conventional manufacturing processes in order to overcome the restrictions of additive manufacturing. To put this into practice, new design guidelines are presented that specifically identify features that can be better manufactured conventionally. Finally, these new design guidelines are evaluated on the basis of an example component being manufactured by machining and laser powder bed fusion, resulting in a reduction of manufacturing costs by 27%

Konstruktive Potentiale einer Mikrostrukturgradierung von topologieoptimierten L-PBF-Bauteilen

The design space of topology optimizations is often limited by installation space limitations and interfaces to other components, which can result in local stress concentrations in the resulting notches. In this paper, the potential of microstructure grading was investigated by means of FE analyses on the basis of two components. In experimental investigations of L-PBF manufactured tensile specimens made of AlSi10Mg, a producible variation range of the Young's modulus from 46 to 62 GPa could be determined. By grading the Young's modulus, a local stress reduction of 18.6% and 25% could be achieved by means of FE analysis, as well as a slight displacement of the stresses around the critical area

Evaluation of Solidification in Powder Bed Fusion using a High Speed Camera

Powder bed fusion using a laser beam (PBF-LB) [1] enables geometrical design freedom to build parts for optimized functionality. Furthermore, PBF-LB allows microstructural design freedom. By controlling the solidification behavior microstructural adaptions can be made to obtain the full potential of the material. As the solidification rates and the thermal gradient depend on the local part geometry, new data-driven approaches, e.g. machine learning (ML), seem to be suitable for local microstructural adaptions. In this work an evaluation concept to analyze the thermal melt pool characteristics based on a high-speed camera is developed. The thermal radiation intensity of the melt pool is used to derive the thermal gradient and combined with an image rate of 41,000 fps the solidification rate is derived. The developed approach provides local data of the solidification for ML-based process adaptions but also serves for part individual quality assurance tasks

Use of Vectorial Tolerances for Direct Representation and Analysis in CAD-systems

AbstractThe paper deals with the representation of vectorial tolerances in the parametric CAD-model using surface-type specific attribute containers, which are attached to the desired nominal surfaces. Since CAD-systems can only evaluate linear, one–dimensional tolerance chains, currently additional CAx-systems are used for tolerance representation, analysis and synthesis. In this paper the representation of vectorial tolerance parameters in the CAD-model is explained. A major motivation for their integration into the CAD-model is the similarity of the vectorial tolerance representation to the B-Rep (Boundary representation) description in current CAD-systems. Furthermore, most engineers think in the standardized tolerance system. So for the user input, a user-controlled translation between the ISO and vectorial tolerances is necessary. The presented approach was realized in a software prototype using the CAD programming interface of SolidWorks.A main focus of the paper is the handling of partially closed tolerance-loops. Most of the CAT-systems only handle open tolerance chains. In contrast, a real system, even if the overall tolerance chain can be considered as an open chain, consists of partially closed tolerance-loops just in the joints or base frames. The developed approach is based on the statically determined placement of a rigid body on three points, where the resulting line of action of the force - even for several parts – goes through the support triangle. Assuming ideal rigid but deviation-affected components the new placement-triangle can be determined. This is a departure from the classical component mates in 3D-CAD that assume geometrically ideal elements. The concept is demonstrated in the article by examples

Process-controlled Grading of the Young's Modulus of AlSi10Mg Components Using L-PBF

Laser Powder Bed Fusion (L-PBF) increases freedom in the design of components and is therefore well suited for the manufacturing of complex geometries tailored to their function. In addition, it is possible to influence the microstructural characteristics of the components by varying the process parameters during the L-PBF process. This allows shifting the load from areas with high stresses to less heavily loaded areas in order to exploit the full potential of the material. For this purpose, the process window in which the Young‘s modulus of the material AlSi10Mg can be varied was investigated. Subsequently, test geometries were analyzed by finite element method with respect to their critical component areas and a design for grading the Young‘s modulus to distribute stress more uniformly was developed. These specimens were then manufactured and compared with components manufactured using homogeneous parameters

Sensorische Maschinenelemente sind Bausteine für die Digitalisierung

Der vorliegende Artikel gibt einen Überblick über die neue Forschungsrichtung der Entwicklung sensorischer Maschinenelemente (SME) und geht auf die Potentiale der Entwicklung von und mit SMEs im Kontext der Digitalisierung von Maschinen und Anlagen ein. Einige Beispiele verdeutlichen die Herausforderungen bei der Interpretation von Messwerten der SMEs und skizziert Lösungsansätze, um mit einer ganzheitlichen Gestaltung der SMEs, ihrer unmittelbaren konstruktiven Umgebung und der informationstechnischen Anbindung an das System die Herausforderungen der Entwicklung von und mit SMEs zu lösen. Der Artikel zeigt auf, welche Potentiale mit Blick auf die großen Herausforderungen der Digitalisierung in den SMEs stecken