SUMMARY Targeting the tumor vasculature with antibody-drug conjugates (ADCs) is a promising anti-cancer strategy that, in order to be realized, must overcome several obstacles, including identification of suitable targets and optimal warheads. Here, we demonstrate that the cell surface protein CD276/B7-H3 is broadly overexpressed by multiple tumor types on both cancer cells and tumor-infiltrating blood vessels, making it a potentially ideal dual-compartment therapeutic target. In preclinical studies CD276-ADCs armed with a conventional MMAE warhead destroyed CD276-positive cancer cells, but were ineffective against tumor vasculature. In contrast, pyrrolobenzodiazepine-conjugated CD276-ADCs killed both cancer cells and tumor vasculature, eradicating large established tumors and metastases, and improving long-term overall survival. CD276 targeted dual-compartment ablation could aid in development of highly selective broad-acting anti-cancer therapies.
The list of ADCs in the clinic continues to grow, bolstered by the success of first two marketed ADCs: ADCETRIS® and Kadcyla®. Currently, there are 40 ADCs in various phases of clinical development. However, only 34 of these have published their structures. Of the 34 disclosed structures, 24 of them use a linkage to the thiol of cysteines on the monoclonal antibody. The remaining 10 candidates utilize chemistry to surface lysines of the antibody. Due to the inherent heterogeneity of conjugation to the multiple lysines or cysteines found in mAbs, significant research efforts are now being directed toward the production of discrete, homogeneous ADC products, via site-specific conjugation. These site-specific conjugations may involve genetic engineering of the mAb to introduce discrete, available cysteines or non-natural amino acids with an orthogonally-reactive functional group handle such as an aldehyde, ketone, azido, or alkynyl tag. These site-specific approaches not only increase the homogeneity of ADCs but also enable novel bio-orthogonal chemistries that utilize reactive moieties other than thiol or amine. This broadens the diversity of linkers that can be utilized which will lead to better linker design in future generations of ADCs.Electronic supplementary materialThe online version of this article (doi:10.1007/s11095-015-1657-7) contains supplementary material, which is available to authorized users.
Access to this document was granted through an Emerald subscription provided by emeraldsrm:198285 [] For AuthorsIf you would like to write for this, or any other Emerald publication, then please use our Emerald for Authors service information about how to choose which publication to write for and submission guidelines are available for all. Please visit www.emeraldinsight.com/authors for more information. About Emerald www.emeraldinsight.comEmerald is a global publisher linking research and practice to the benefit of society. The company manages a portfolio of more than 290 journals and over 2,350 books and book series volumes, as well as providing an extensive range of online products and additional customer resources and services.Emerald is both COUNTER 4 and TRANSFER compliant. The organization is a partner of the Committee on Publication Ethics (COPE) and also works with Portico and the LOCKSS initiative for digital archive preservation. AbstractPurpose -In the ever increasing competition in the employment market, an organization's need to become a "great place to work" has gained significant momentum. Employer branding has thus emerged as an essential management practice employed by the organization to create its image as desirable employer in the eyes of prospective employees. The purpose of this paper is to highlight the understanding of employer branding through the eyes of "potential" young employees in Delhi and North Central Region, India. The results presented in this paper throw light on the perceived importance of employer branding among the prospective employees via analysis of various branding factors chosen for the study. The study results report that the perceived significance of employer branding factors differs mainly across gender and age of prospective employees. Notably, public and private sectors are being perceived significantly different by the potential job applicants on employer branding factors. Thus, this paper presents important findings enabling employers to build brand value and an attractive reputation in the job market so as to attract and retain the best talent. Design/methodology/approach -Survey methodology was used to test the hypothesis. The sample was selected from Delhi and National Capital Region (NCR) primarily from the students of business schools who were randomly selected to fill in the questionnaire. As they are the potential hires, it seemed appropriate to know their preference of employer branding factors. They are ready to join the corporations therefore, data extracted would be much more suitable as they can throw light on their immediate preferences and provide insight into the research study. For collection of data an online structured questionnaire was administered. A total of 270 questionnaires were administered and 239 filled questionnaires were received. Findings -From the results it can be seen that private sector emerged as preferred sector of choice for the majority of potential employees. However, there are some factors which are handled well in pr...
The fine‐tuning of the protecting groups and the glycosidation conditions were the key to the successful coupling of the carbohydrate units and vancomycin aglycon in the last steps of the total synthesis of vancomycin 1. The aglycon was converted into a suitably protected acceptor and the sugar donors were sequentially attached. Removal of all the protecting groups gave synthetic vancomycin that was indentical to the natural product (1H and 13C NMR, HPLC).
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