On April 22, 2016 CRT and The University of Copenhagen reported to have signed a deal with Switzerland-based ADC Therapeutics SA (ADCT) to license antibodies against a cancer-specific cell surface protein (Press release, Cancer Research Technology, 22 22, 2016, View Source [SID1234523187]). The antibodies will be used by ADCT to develop a novel Antibody Drug Conjugate (ADC) that could potentially treat a range of cancers.

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The antibodies – jointly developed by Cancer Research UK and the University of Copenhagen scientists – target a protein overexpressed on the surface of some cancer cells, which is not expressed on healthy cells.

ADCT intends to incorporate the antibodies into a novel ADC therapeutic using its proprietary linker and pyrrolobenzodiazepine (PBD) cytotoxic warhead technology*. The antibodies are expected to selectively target the PBD cytotoxic to cancer cells, sparing normal tissue.

Thomas Bjørnholm, Pro-Vice-chancellor for Research and Innovation, the University of Copenhagen, said: "We are very pleased and proud that research from the University’s Faculty of Health and Medical Sciences has been licensed to ADCT for the development of new cancer therapeutics. Our mission as a public university is precisely to make sure that our leading-edge research is disseminated and is taken to the market together with commercial partners for the benefit of society at large."

Dr Keith Blundy, Cancer Research Technology’s chief executive, said: "This important license deal brings together CRT’s access to world class research and ADCT’s cutting edge technology to develop exciting new therapeutics for cancer.

"We hope this agreement will pave the way for promising new ways to treat a range of cancers in a targeted way without damaging healthy tissue."

Skin allergy, in particular, allergic contact dermatitis and irritant contact dermatitis, are common occupational and environmental health problems affecting the quality of life of a significant proportion of the world population. Since all new ingredients to be incorporated into a product are potential skin allergens, it is essential that these ingredients be first tested for their allergenic potential. However, despite the considerable effort using animal models to understand the underlying mechanism of skin sensitization, to date, the molecular and cellular responses due to skin contact with sensitizers are still not fully understood. To replace animal testing and to improve the prediction of skin sensitization, significant attention has been directed to the use of reconstructed organotypic in vitro models of human skin. Here we describe a miniaturized immune competent in vitro model of human skin based on 3D co-culture of immortalized human keratinocytes (HaCaT) as a model of the epidermis barrier and human leukemic monocyte lymphoma cell line (U937) as a model of human dendritic cells. The biological model was fitted in a microfluidic-based cell culture system that provides a dynamic cellular environment that mimics the in vivo environment of skin. The dynamic perfusion of culture media significantly improved the tight junction formation as evidenced by measuring higher values of TEER compared to static culture. This setting also maintained the high viability of cells over extended periods of time up to 17 days. The perfusion-based culture also allows growth of the cells at the air-liquid interface by exposing the apical side of the cells to air while providing the cell nutrients through a basolateral fluidic compartment. The microsystem has been evaluated to investigate the effect of the chemical and physical (UV irradiation) stimulation on the skin barrier (i.e. the TJ integrity). Three-tiered culture differential stimulation allowed the investigation of the role of the keratinocyte layer as a protection barrier to chemical/biological hazards.

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The high rate of failure of new agents in oncology clinical trials indicates a weak understanding of the complexity of human cancer. Recent understanding of the mechanisms underlying castration resistance in prostate cancer led to the development of new agents targeting the androgen receptor pathway; however, their effectiveness is limited. Hence, there is a need for experimental systems that are able to better reproduce the biological diversity of prostate cancer in preclinical settings. In this study, we established a unique patient-derived xenograft (PDX) model to identify biomarkers for treatment efficacy and resistance and better understand prostate cancer biology.
A prostate cancer tissue sample from a Japanese patient was transplanted subcutaneously into male, severe combined immune-deficient (SCID) mice and this PDX mouse model was named KUCaP3. Sequential tumor volume changes were observed before and after castration. Androgen receptor (AR), prostate-specific antigen (PSA), and other molecular markers were examined immunohistochemically. Sequence analysis of AR was also performed to detect mutations. Proteomic analysis of cyst fluid and sera samples of KUCaP3 mice were analyzed by mass spectrometry (MS).
KUCaP3 cell line, derived from human tissue, was successfully and serially passaged in vivo with approximately 60% take rate. KUCaP3 exhibited cyst formation, showed androgen-dependent growth initially, and developed castration-resistant growth several months after castration of the mice. Immunohistochemical analysis showed that KUCaP3 was positive for AR, PSA, CK18, and α-methyl acyl-coenzyme A racemase, but negative for CK5/6 and ERG. The AR gene in KUCaP3 cells contained a substitution from CAT (histidine) to TAT (tyrosine) at the nucleotide positions corresponding to codon 875 (H875Y) in the ligand-binding domain. Chemiluminescent immunoassay revealed higher levels of PSA in cystic fluid and the serum of KUCaP3-bearing mice. MS analysis detected 23 proteins of human origin in cystic fluids of KUCaP3.
We developed KUCaP3, an androgen-dependent PDX model with cyst formation. Several proteins including PSA were detected in the cystic fluid and sera of tumor-bearing mice. This original PDX model has the potential to be used as a clinically relevant model to evaluate molecular markers for prostate cancer diagnosis and treatment. Prostate © 2016 Wiley Periodicals, Inc.
© 2016 Wiley Periodicals, Inc.

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(Filing, 10-K, Protalix, 2015, APR 22, 2016, View Source [SID:1234511363])

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In recent years, various outcome adaptive randomization (AR) methods have been used to conduct comparative clinical trials. Rather than randomizing patients equally between treatments, outcome AR uses the accumulating data to unbalance the randomization probabilities in favor of the treatment arm that currently is superior empirically. This is motivated by the idea that, on average, more patients in the trial will be given the treatment that is truly superior, so AR is ethically more desirable than equal randomization. AR remains controversial, however, and some of its properties are not well understood by the clinical trials community.
Computer simulation was used to evaluate properties of a 200-patient clinical trial conducted using one of four Bayesian AR methods and compare them to an equally randomized group sequential design.
Outcome AR has several undesirable properties. These include a high probability of a sample size imbalance in the wrong direction, which might be surprising to nonstatisticians, wherein many more patients are assigned to the inferior treatment arm, the opposite of the intended effect. Compared with an equally randomized design, outcome AR produces less reliable final inferences, including a greatly overestimated actual treatment effect difference and smaller power to detect a treatment difference. This estimation bias becomes much larger if the prognosis of the accrued patients either improves or worsens systematically during the trial.
AR produces inferential problems that decrease potential benefit to future patients, and may decrease benefit to patients enrolled in the trial. These problems should be weighed against its putative ethical benefit. For randomized comparative trials to obtain confirmatory comparisons, designs with fixed randomization probabilities and group sequential decision rules appear to be preferable to AR, scientifically, and ethically.
© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].

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