The fibroblast activation protein (FAP) is selectively expressed on activated fibroblasts of the tumor stroma on more than 90% of lung, breast and colon carcinomas. The high prevalence and abundance of FAP stroma make it a promising target for in vivo diagnosis and therapy of a variety of carcinomas. We describe the humanization of the murine FAP-specific MAb, F19, which has already been clinically used for in vivo diagnostic purposes. Using phage display technology and human V-repertoires, VL and VH regions of F19 were replaced by analogous human V-regions while retaining the original HCDR3 sequence in order to maintain F19 epitope specificity. The resulting human single-chain fragments of immunoglobulin variable regions (scFv 34, scFv 18) showed affinities of 6 nM on cell membrane-bound FAP. scFv 34 was expressed as a bivalent minibody (Mb 34). The antigen-binding characteristics of Mb 34 were comparable to the parental and a complementarity-determining region (CDR)-grafted version of F19. This was revealed by binding competition studies, FACS analyses and immunohistochemistry on various tumor samples including breast, colon and lung carcino-mas. Importantly, compared with the CDR-grafted human-ized scFv version of F19, the V-regions of the selected human scFv 34 showed sequence identity with the parental antibody (Ab) only over the short, 15-amino acid long HCDR3. Thus, a largely reduced xenoantigenic potential is expected. These human Ab derivatives are suitable to develop novel therapeutic concepts with broad applicability for a wide variety of histological carcinomas based on tumor stroma targeting. The growth of tumors (diameter 1-2 mm) is dependent on angiogenesis and blood supply, postulated already by Folkman in 1971 1 and experimentally proven in later years. 2,3 Moreover, a correlation between the degree of tumor vascularization and the formation of metastases has been observed. 4 Cells of the tumor-supplying tissue, in particular the endothelial cells of the tumor vasculature and stromal fibroblasts, are regarded as expedient targets. This is because they are non-transformed and thus considered as genetically stable and shared by practically all solid tumors. Markers selectively expressed on these cells are exploited for in vivo diagnostic and novel therapeutic approaches based on specific antibodies (tumor stroma targeting). The feasibility of this strategy is supported by studies with animal tumor models. 5,6 The FAP is considered as a suitable Ag for a stroma-targeting approach for several reasons: (1) in more than 90% of all epithelial tumors including lung, colorectal and breast carcinomas (primary tumors and metastases), the tumor stroma is FAP ; in post-natal non-tumor tissues, FAP is expressed during wound healing and on pancreatic cells; (2) stromal fibroblasts are non-transformed cells, making the rapid emergence of Ag loss variants and therapy resistance unlikely; (3) the FAP stromal compartment, commonly contributing approximately 50% to 90% of the tumor mass, presents an abundant target...
Given their intrinsic features, adaptive facades are required to strictly satisfy rigid structural performances, in addition to typical insulation, thermal and energy requirements. These include a minimum of safety and serviceability levels under ordinary design loads, durability, robustness, fire resistance, capacity to sustain severe seismic events or other natural hazards, etc. The overall design process of adaptive facades may include further challenges and uncertainties especially in the case of complex assemblies, where even multiple combinations of material-related phenomena, kinematic effects, geometrical and mechanical characteristics could take place. In this context, experimental testing at the component and / or at the full-scale assembly level has a fundamental role, to prove that all the expected performance parameters are properly fulfilled.
The experimental setup implements a simplified PASSYS test cell construction, which is combined with a detailed simulation to reduce measurement effort. To analyze the cell’s dynamic behavior, the test cell was closely monitored with thermal sensors, and different static and dynamic heating modes were applied during a three-week calibration period. Co-heating tests were performed for steady-state measurements and cyclic heating periods account for the transient behavior of the test cell. The cells response was compared to the results of transient simulations with the software packet Modelica. The equation based Modelica framework allowed a detailed transient thermal simulation of the test cell’s dynamic to be set up that shows close agreement with the measurements. In addition, the flexibility of Modelica allowed unforeseen events affecting the experimental setup to be replicated, thereby ensuring an uninterrupted heat flow history of all surfaces. More than 96% of the predicted air temperatures (1 min resolution) match the experimental values within an error band of ±1.5 K, and 90% of all predictions are within ±1.0 K.
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