Dextramabs: A Novel Format of Antibody-Drug Conjugates Featuring a Multivalent Polysaccharide Scaffold

Antibody-drug conjugates (ADCs) are multicomponent biomolecules that have emerged as a powerful tool for targeted tumor therapy. Combining specific binding of an immunoglobulin with toxic properties of a payload, they however often suffer from poor hydrophilicity when loaded with a high amount of toxins. To address these issues simultaneously, we developed dextramabs, a novel class of hybrid antibody-drug conjugates. In these architectures, the therapeutic antibody trastuzumab is equipped with a multivalent dextran polysaccharide that enables efficient loading with a potent toxin in a controllable fashion. Our modular chemoenzymatic approach provides an access to synthetic dextramabs bearing monomethyl auristatin as releasable cytotoxic cargo. They possess high drug-to-antibody ratios, remarkable hydrophilicity, and high toxicity in vitro.     

On the nonexistence of certain Hughes generalized quadrangles

In this paper, we prove that the Hermitian quadrangle is the unique generalized quadrangle Γ of order (q ², q ³) containing some subquadrangle of order (q ², q) isomorphic to such that every central elation of the subquadrangle is induced by a collineation of Γ. Dedicated to Dan Hughes on the occasion of his 80th birthday.     

Some Characterizations of Finite Hermitian Veroneseans

We characterize the finite Veronesean of all Hermitian varieties of PG(n,q²) as the unique representation of PG(n,q²) in PG(d,q), d n(n+2), where points and lines of PG(n,q²) are represented by points and ovoids of solids, respectively, of PG(d,q), with the only condition that the point set of PG(d,q) corresponding to the point set of PG(n,q²) generates PG(d,q). Using this result for n=2, we show that is characterized by the following properties: (1) ; (2) each hyperplane of PG(8,q) meets in q²+1, q³+1 or q³+q²+1 points; (3) each solid of PG(8,q) having at least q+3 points in common with shares exactly q²+1 points with it.51E24     

The resolvent algebra: A new approach to canonical quantum systems

The standard C^∗-algebraic version of the algebra of canonical commutation relations, the Weyl algebra, frequently causes difficulties in applications since it neither admits the formulation of physically interesting dynamical laws nor does it incorporate pertinent physical observables such as (bounded functions of) the Hamiltonian. Here a novel C^∗-algebra of the canonical commutation relations is presented which does not suffer from such problems. It is based on the resolvents of the canonical operators and their algebraic relations. The resulting C^∗-algebra, the resolvent algebra, is shown to have many desirable analytic properties and the regularity structure of its representations is surprisingly simple. Moreover, the resolvent algebra is a convenient framework for applications to interacting and to constrained quantum systems, as we demonstrate by several examples.     

Interatomic electronic decay driven by nuclear motion

The interatomic electronic decay after inner-valence ionization of a neon atom by a single photon in a neon-helium dimer is investigated. The excited neon atom relaxes via interatomic Coulombic decay and the excess energy is transferred to the helium atom and ionizes it. We show that the decay process is only possible if the dimer's bond stretches up to 6.2 ?, i.e., to more than twice the equilibrium interatomic distance of the neutral dimer. Thus, it is demonstrated that the electronic decay, taking place at such long distances, is driven by the nuclear motion.     

NMR elucidation of a novel (S)-pentacyclo-undecane bis-(4-phenyloxazoline) ligand and related derivatives

The NMR elucidation of a novel ligand (S)-pentacyclo-undecane bis-(4-phenyloxazoline) and related pentacyclo-undecane (PCU) derivatives is reported. Two-dimensional NMR proved to be a powerful technique in overcoming the difficulties associated with the elucidation of these compounds when only one-dimensional NMR data is utilized. A chiral substituent was introduced to both 'arms' of the PCU skeleton to produce derivatives 1-3. These derivatives display C(1) symmetry with all thecage atoms being nonequivalent. Owing to overlapping of peaks in the (1)H spectra, identification of these diastereomeric protons was very difficult. The (13)C spectra gave rise to clear splitting of the nonequivalent carbons. This is unusual compared to similar PCU derivatives with chiral substituents as splitting of all the diastereomeric cage carbons has not yet been reported. Nuclear Overhauser enhancement spectroscopy (NOESY) correlations of derivatives 1-3 confirm the different conformations of the molecule in which the side 'arms' occupy different orientations with respect to cage moiety.     

Visible-Light-Induced Control over Reversible Single-Chain Nanoparticle Folding

We introduce a class of single-chain nanoparticles (SCNPs) that respond to visible light (λ_max=415 nm) with complete unfolding from their compact structure into linear chain analogues. The initial folding is achieved by a simple esterification reaction of the polymer backbone constituted of acrylic acid and polyethylene glycol carrying monomer units, introducing bimane moieties, which allow for the photochemical unfolding, reversing the ester-bond formation. The compaction and the light driven unfolding proceed cleanly and are readily followed by size exclusion chromatography (SEC) and diffusion ordered NMR spectroscopy (DOSY), monitoring the change in the hydrodynamic radius (R_H). Importantly, the folding reaction and the light-induced unfolding are reversible, supported by the high conversion of the photo cleavage. As the unfolding reaction occurs in aqueous systems, the system holds promise for controlling the unfolding of SCNPs in biological environments.     

Largazole: from discovery to broad-spectrum therapy

The cyclic depsipeptide largazole from a cyanobacterium of the genus Symploca is a marine natural product with a novel chemical scaffold and potently inhibits class I histone deacetylases (HDACs). Largazole possesses highly differential growth-inhibitory activity, preferentially targeting transformed over non-transformed cells. The intriguing structure and biological activity of largazole have attracted strong interest from the synthetic chemistry community to establish synthetic routes to largazole and to investigate its potential as a cancer therapeutic. This Highlight surveys recent advances in this area with a focus on the discovery, synthesis, target identification, structure-activity relationships, HDAC8-largazole thiol crystal structure, and biological studies, including in vivo anticancer and osteogenic activities.     

Crystallographic recognition controls peptide binding for bio-based nanomaterials

The ability to control the size, shape, composition, and activity of nanomaterials presents a formidable challenge. Peptide approaches represent new avenues to achieve such control at the synthetic level; however, the critical interactions at the bio/nano interface that direct such precision remain poorly understood. Here we present evidence to suggest that materials-directing peptides bind at specific time points during Pd nanoparticle (NP) growth, dictated by material crystallinity. As such surfaces are presented, rapid peptide binding occurs, resulting in the stabilization and size control of single-crystal NPs. Such specificity suggests that peptides could be engineered to direct the structure of nanomaterials at the atomic level, thus enhancing their activity.