Hepatocellular Carcinoma: Epidemiology and Molecular Carcinogenesis

Evolution of Protein Molecules

Solid tumours are an enormous cancer burden and a major therapeutic challenge. The cancer stem cell (CSC) hypothesis provides an attractive cellular mechanism to account for the therapeutic refractoriness and dormant behaviour exhibited by many of these tumours. There is increasing evidence that diverse solid tumours are hierarchically organized and sustained by a distinct subpopulation of CSCs. Direct evidence for the CSC hypothesis has recently emerged from mouse models of epithelial tumorigenesis, although alternative models of heterogeneity also seem to apply. The clinical relevance of CSCs remains a fundamental issue but preliminary findings indicate that specific targeting may be possible.

Cancer stem cells in solid tumours: accumulating evidence and unresolved questions

Infectious Diseases Society of America.

MYC on the Path to Cancer

The invention relates to antibodies against the tumor-associated antigen CD33 and their use for the immunotargeting of CD33-positive cells. The antibodies according to the invention are suitable for use in the field of medicine, pharmacy and in biomedical research. According to the invention the object is achieved by new anti-CD33 antibodies which contain the complementary determining regions (CDRs) defined in claim 1. The antibodies according to the invention are distinguished by a high affinity for human CD33, which is of the order of 10 mol / l. Due to the high affinity, the CDR sequences according to the invention are particularly suitable for the production of recombinant fragments (such as scFv fragments or bispecific antibodies) and for immunotargeting. The invention further comprises the use of an antibody according to the invention for the production of a medicament for therapeutic and / or diagnostic use in diseases which are associated with the expression of CD33, in particular in acute myeloid leukemia (AML). The invention thus also encompasses a pharmaceutical composition which contains one or more antibodies according to the invention in association with a pharmaceutically acceptable diluent or carrier.

Anti-CD33 antibodies and their use for immuno-targeting in the treatment of CD33-associated diseases

Adaptor chimeric antigen receptor (CAR) T-cell therapy offers solutions for improved safety and antigen escape, which represent main obstacles for the clinical translation of CAR T-cell therapy in myeloid malignancies. The adaptor CAR T-cell platform 'UniCAR' is currently under early clinical investigation. Recently, the first proof of concept of a well-tolerated, rapidly switchable, CD123-directed UniCAR T-cell product treating patients with acute myeloid leukaemia (AML) was reported. Relapsed and refractory AML is prone to high plasticity under therapy pressure targeting one single tumour antigen. Thus, targeting of multiple tumour antigens seems to be required to achieve durable anti-tumour responses, underlining the need to further design alternative AML-specific target modules (TM) for the UniCAR platform. We here present the preclinical development of a novel FMS-like tyrosine kinase 3 (FLT3)-directed UniCAR T-cell therapy, which is highly effective for in vitro killing of both AML cell lines and primary AML samples. Furthermore, we show in vivo functionality in a murine xenograft model. PET analyses further demonstrate a short serum half-life of FLT3 TMs, which will enable a rapid on/off switch of UniCAR T cells. Overall, the presented preclinical data encourage the further development and clinical translation of FLT3-specific UniCAR T cells for the therapy of AML.

FLT3-directed UniCAR T-cell therapy of acute myeloid leukaemia.

Functional interaction between cancer cells and the surrounding microenvironment is still not sufficiently understood, which motivates the tremendous interest for the development of numerous in vitro tumor models. Diverse parameters, for example, transport of nutrients and metabolites, availability of space in the confinement, etc. make an impact on the size, shape, and metabolism of the tumoroids. We demonstrate the fluidics‐based low‐cost methodology to reproducibly generate the alginate and alginate‐chitosan microcapsules and apply it to grow human hepatoma (HepG2) spheroids of different dimensions and geometries. Focusing specifically on the composition and thickness of the hydrogel shell, permeability of the microcapsules was selectively tuned. The diffusion of the selected benchmark molecules through the shell has been systematically investigated using both, experiments and simulations, which is essential to ensure efficient mass transfer and/or filtering of the biochemical species. Metabolic activity of spheroids in microcapsules was confirmed by tracking the turnover of testosterone to androstenedione with chromatography studies in a metabolic assay. Depending on available space, phenotypically different 3D cell assemblies have been observed inside the capsules, varying in the tightness of cell aggregations and their shapes. Conclusively, we believe that our system with the facile tuning of the shell thickness and permeability, represents a promising platform for studying the formation of cancer spheroids and their functional interaction with the surrounding microenvironment.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/biot.202200365

Shell engineering in soft alginate‐based capsules for culturing liver spheroids

Spatially resolved field emission measurements represent an important factor in further development of existing field emitter concepts. In this work, we present a novel approach that allows quantitative analysis of individual emission spots from integral current-voltage measurements using a low-cost and commercially available CMOS camera. By combining different exposure times to extrapolate oversaturated and underexposed pixels, a near congruence of integral current and image brightness is shown. The extrapolation also allows parallel investigation of all individual tips participating in the total current with currents ranging from a few nanoampere to one microampere per tip. The sensitivity, which is determined by the integral brightness-to-current ratio, remains unchanged within the measurement accuracy even after ten full measurement cycles. Using a point detection algorithm, the proportional current load of each individual tip of the field emitter array is analyzed and compared at different times during the initial measurement cycle. Together with the extracted I–V curves of single emission spots from the integral measurement, the results indicate the effect of premature burnout of particularly sharp tips during conditioning of the emitter. 

In situ quantitative field emission imaging using a low-cost CMOS imaging sensor

Die Erfindung betrifft eine Zusammensetzung, die mindestens einen anti-slan Antikorper enthalt. Ferner betrifft die Erfindung die diagnostische und therapeutische Verwendung dieser Zusammensetzung. Aufgabe der Erfindung ist es, ein Therapiesystem bereitzustellen, dass dazu geeignet ist, Co-Stimuli, die DC aktivieren, gleichzeitig mit dem Antigen gezielt an slan-DC zu transportieren und anti-slan Antikorper bereitzustellen, die fur diese Anwendung geeignet sind. Die Aufgabe wird erfindungsgemas durch eine Zusammensetzung gelost, die folgende Bestandteile umfasst: a) mindestens einen anti-slan Antikorper, b) mindestens eine an einen Liganden bindende Bindungseinheit, wobei der Ligand die Aktivierung von besagten dendritischen Zellen bewirkt, und c) mindestens ein Antigen. Die erfindungsgemasen Zusammensetzungen eignen sich fur eine therapeutische Anwendung. Ferner umfasst die Erfindung anti-slan Antikorper, welche CDRs mit folgenden Sequenzen aufweisen: variable Region der schweren Kette: CDR1 (SEQ ID No. 1), CDR2 (SEQ ID No. 2), wobei Xaa ausgewahlt ist aus M, L, F, oder I, vorzugsweise aus M oder I, CDR3 (SEQ ID No. 5) und variable Region der leichten Kette: CDR1 (SEQ ID No. 6), wobei Xaa ausgewahlt ist aus S, T, N, Q, H, K oder R, vorzugsweise aus S oder N, CDR2 (SEQ ID No. 9) und CDR3 (SEQ ID No. 10).

Michael Bachmann

Papers

Anti-CD33 antibodies and their use for immuno-targeting in the treatment of CD33-associated diseases

FLT3-directed UniCAR T-cell therapy of acute myeloid leukaemia.

Shell engineering in soft alginate‐based capsules for culturing liver spheroids

In situ quantitative field emission imaging using a low-cost CMOS imaging sensor

Antikörper gegen 6-sulfo LacNAc positive humane dendritische Zellen und deren Verwendung