A Phase 1 First-in-Human Pharmacokinetic and Pharmacodynamic Study of JNJ-64264681, a Covalent Inhibitor of Bruton's Tyrosine Kinase.

JNJ-64264681 is an irreversible covalent inhibitor of Bruton's tyrosine kinase. This phase 1, first-in-human, 2-part (single-ascending dose [SAD]; multiple-ascending dose [MAD]) study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD; Bruton's tyrosine kinase occupancy [BTKO]) of JNJ-64264681 oral solution in healthy participants. For SAD (N = 78), 6 increasing doses of JNJ-64264681 (4-400 mg) or placebo were evaluated in fasted males.

Approaches to improve drug tolerance and target tolerance in the assessment of neutralizing anti-drug antibodies.

Neutralizing anti-drug antibody (NAb) assays are inherently prone to the interference from drug and its soluble target, potentially resulting in erroneous results. An effective approach to improve drug tolerance of an NAb assay is pretreatment of samples with acid to dissociate immune complexes of NAb and drug, followed by separating NAbs from circulating drug before testing them in the assay. The acid pretreatment conditions were optimized to improve drug tolerance of cell-based and non-cell-based NAb assays.

Dorsal-B, a splice variant of the Drosophila factor Dorsal, is a novel Rel/NF-kappaB transcriptional activator.

The Drosophila transcription factor Dorsal, a member of the Rel/NF-kappaB family of proteins, plays a key role in the establishment of dorsoventral polarity in the early embryo and is also involved in the immune response. Here, we present evidence that the primary transcript of dorsal can be alternatively spliced, generating Dorsal-B, a new Rel/NF-kappaB family member. Dorsal and Dorsal-B are identical in the N-terminal region, which comprises both a DNA-binding domain and a dimerization domain.

A LexA mutant repressor with a relaxed inter-domain linker.

The LexA protein is part of a large family of prokaryotic transcriptional repressors that contain an amino-terminal DNA binding domain and a carboxy-terminal dimerization domain. These domains are separated by a linker or hinge region, which is generally considered to be rather flexible and unconstrained. So far, no structure of any of the full-length repressors is available.