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.
As part of a program directed at the development of palladium-and nickel-catalyzed couplings of alkyl electrophiles, 1 we have been exploring the possibility of achieving a variant of the Heck reaction wherein an alkyl, rather than an aryl, electrophile is coupled with an olefin. In an initial study, we were pleased to discover that such a transformation can indeed be accomplished, albeit in very poor yield (1.2%; eq 1). Interestingly, however, control reactions established that carbon-carbon bond formation proceeds more efficiently in the absence of palladium (24%; eq 1)! Our mechanistic hypothesis for this unanticipated carbene-catalyzed cyclization is outlined in Figure 1. 2,3 Thus, the catalyst (Nu:) adds to the electrophilic β carbon of the α, β-unsaturated ester, generating an enolate (A). Tautomerization then affords B ,4 in which the β carbon is now nucleophilic (umpolung5 ,6 ). An intramolecular S N 2 reaction provides C, which undergoes elimination to furnish the observed product and to regenerate the catalyst (Nu:).For most of the previously described nucleophile-catalyzed reactions of Michael acceptors, the initial adduct (e.g., A) reacts with electrophiles in the α position (e.g., the Morita-BaylisHillman reaction 7 ). Indeed, we have only been able to identify one previous report of a process wherein conjugate addition of a catalyst leads to the β carbon serving as a nucleophile. 8 Furthermore, an interesting contrast is provided by the recent work of Krafft, who has established that enones/enals that bear pendant halides undergo cyclization in the α position when treated with stoichiometric PMe 3 or PBu 3 and then KOH (e.g., eq 2). 9
Ferroelectric hafnium zirconium oxide holds great promise for a broad spectrum of complementary metal–oxide–semiconductor (CMOS) compatible and scaled microelectronic applications, including memory, low-voltage transistors, and infrared sensors, among others. An outstanding challenge hindering the implementation of this material is polarization instability during field cycling. In this study, the nanoscale phenomena contributing to both polarization fatigue and wake-up are reported. Using synchrotron X-ray diffraction, the conversion of non-polar tetragonal and polar orthorhombic phases to a non-polar monoclinic phase while field cycling devices comprising noble metal contacts is observed. This phase exchange accompanies a diminishing ferroelectric remanent polarization and provides device-scale crystallographic evidence of phase exchange leading to ferroelectric fatigue in these structures. A reduction in the full width at half-maximum of the superimposed tetragonal (101) and orthorhombic (111) diffraction reflections is observed to accompany wake-up in structures comprising tantalum nitride and tungsten electrodes. Combined with polarization and relative permittivity measurements, the observed peak narrowing and a shift in position to lower angles is attributed, in part, to a phase exchange of the non-polar tetragonal to the polar orthorhombic phase during wake-up. These results provide insight into the role of electrodes in the performance of hafnium oxide-based ferroelectrics and mechanisms driving wake-up and fatigue, and demonstrate a non-destructive means to characterize the phase changes accompanying polarization instabilities.
A stereoconvergent method for the catalytic asymmetric Negishi cross-coupling of racemic secondary propargylic halides with arylzinc reagents has been developed. Neither family of compounds has previously been shown to be a suitable partner in such coupling processes. From a practical point of view, it is noteworthy that the catalyst components (NiCl2·glyme and pybox ligand 1) are commercially available.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.