Compact hydrophilic electrophiles enable highly efficacious high DAR ADCs with excellent PK profile.

The recent success of antibody-drug conjugates (ADC), exemplified by seven new FDA-approvals within three years, has led to increased attention for antibody based targeted therapeutics and fueled efforts to develop new drug-linker technologies for improved next generation ADCs. We present a highly efficient phosphonamidate-based conjugation handle that combines a discrete hydrophilic PEG-substituent, an established linker-payload and a cysteine-selective electrophile in one compact building block. This reactive entity provides homogeneous ADCs with a high drug-to-antibody ratio (DAR) of 8 in a one-pot reduction and alkylation protocol from non-engineered antibodies.

PARP1 Inhibitor and Trabectedin Combination Does Not Increase Tumor Mutational Burden in Advanced Sarcomas-A Preclinical and Translational Study.

Drug-induced tumor mutational burden (TMB) may contribute to unleashing the immune response in relatively "immune-cold" tumors, such as sarcomas. We previously showed that PARP1 inhibition perpetuates the DNA damage induced by the chemotherapeutic agent trabectedin in both preclinical models and sarcoma patients. In the present work, we explored acquired genetic changes in DNA repair genes, mutational signatures, and TMB in a translational platform composed of cell lines, xenografts, and tumor samples from patients treated with trabectedin and olaparib combination, compared to cells treated with temozolomide, an alkylating agent that induces hypermutation.

The Health-Related Quality of Life of Sarcoma Patients and Survivors in Germany-Cross-Sectional Results of a Nationwide Observational Study (PROSa).

Sarcomas are rare cancers with high heterogeneity in terms of type, location, and treatment. The health-related quality of life (HRQoL) of sarcoma patients has rarely been investigated and is the subject of this analysis. Adult sarcoma patients and survivors were assessed between September 2017 and February 2019 in 39 study centers in Germany using standardized, validated questionnaires (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)).

N-Hydroxysuccinimide-Modified Ethynylphosphonamidates Enable the Synthesis of Configurationally Defined Protein Conjugates.

Herein, the application of N-hydroxysuccinimide-modified phosphonamidate building blocks for the incorporation of cysteine-selective ethynylphosphonamidates into lysine residues of proteins, followed by thiol addition with small molecules and proteins, is reported. It is demonstrated that the building blocks significantly lower undesired homo-crosslinking side products that can occur with commonly applied succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) under physiological pH. The previously demonstrated stability of the phosphonamidate moiety additionally solves the problem of premature maleimide hydrolysis, which can hamper the efficiency of subsequent thiol addition.

Ethynylphosphonamidates for the Rapid and Cysteine-Selective Generation of Efficacious Antibody-Drug Conjugates.

Requirements for novel bioconjugation reactions for the synthesis of antibody-drug conjugates (ADCs) are exceptionally high, since conjugation selectivity as well as the stability and hydrophobicity of linkers and payloads drastically influence the performance and safety profile of the final product. We report Cys-selective ethynylphosphonamidates as new reagents for the rapid generation of efficacious ADCs from native non-engineered monoclonal antibodies through a simple one-pot reduction and alkylation. Ethynylphosphonamidates can be easily substituted with hydrophilic residues, giving rise to electrophilic labeling reagents with tunable solubility properties.

International Union of Basic and Clinical Pharmacology CIV: The Neurobiology of Treatment-resistant Depression: From Antidepressant Classifications to Novel Pharmacological Targets.

Major depressive disorder is one of the most prevalent and life-threatening forms of mental illnesses and a major cause of morbidity worldwide. Currently available antidepressants are effective for most patients, although around 30% are considered treatment resistant (TRD), a condition that is associated with a significant impairment of cognitive function and poor quality of life. In this respect, the identification of the molecular mechanisms contributing to TRD represents an essential step for the design of novel and more efficacious drugs able to modify the clinical course of this disorder and increase remission rates in clinical practice.

Search for next-to-minimal supersymmetric Higgs bosons in the h --> aa --> micromicromicromicro, micromicrotautau channels using pp[over] collisions at sqrt[s] = 1.96 TeV.

We report on a first search for production of the lightest neutral CP-even Higgs boson (h) in the next-to-minimal supersymmetric standard model, where h decays to a pair of neutral pseudoscalar Higgs bosons (a), using 4.2 fb;{-1} of data recorded with the D0 detector at Fermilab. The a bosons are required to either both decay to micro;{+}micro;{-} or one to micro;{+}micro;{-} and the other to tau;{+}tau;{-}.

Measurement of muon neutrino quasielastic scattering on carbon.

The observation of neutrino oscillations is clear evidence for physics beyond the standard model. To make precise measurements of this phenomenon, neutrino oscillation experiments, including MiniBooNE, require an accurate description of neutrino charged current quasielastic (CCQE) cross sections to predict signal samples. Using a high-statistics sample of nu_(mu) CCQE events, MiniBooNE finds that a simple Fermi gas model, with appropriate adjustments, accurately characterizes the CCQE events observed in a carbon-based detector.

Cellular fatty acid composition of Campylobacter pylori from primates and ferrets compared with those of other campylobacters.

The cellular fatty acid profiles of newly described campylobacters were determined on a polar, capillary column. Six isolates of the gastric spiral organism, Campylobacter pylori subsp. mustelae, from ferrets from Australia, England, and the United States were all found to have a similar fatty acid profile which was different from that of C.