For many antibodies, each antigen-binding site binds to only one antigen molecule during the antibody's lifetime in plasma. To increase the number of cycles of antigen binding and lysosomal degradation, we engineered tocilizumab (Actemra), an antibody against the IL-6 receptor (IL-6R), to rapidly dissociate from IL-6R within the acidic environment of the endosome (pH 6.0) while maintaining its binding affinity to IL-6R in plasma (pH 7.4). Studies using normal mice and mice expressing human IL-6R suggested that this pH-dependent IL-6R dissociation within the acidic environment of the endosome resulted in lysosomal degradation of the previously bound IL-6R while releasing the free antibody back to the plasma to bind another IL-6R molecule. In cynomolgus monkeys, an antibody with pH-dependent antigen binding, but not an affinity-matured variant, significantly improved the pharmacokinetics and duration of C-reactive protein inhibition. Engineering pH dependency into the interactions of therapeutic antibodies with their targets may enable them to be delivered less frequently or at lower doses.

No abstract

This study is based on the dissections of 645 pelvic halves of Japanese cadavers. The branching of the internal iliac artery was classified according to Adachi's classification (1928) , and the data was compared with previous reports. Type I was predominant in this , as well as, in previous studies. During the course of the present study, some branching forms were different from the types in Adachi's classification. Therefore, this classification was modified into 5 types and 19 groups. Type I-Group 1 was most frequently observed in the modified Adachi's classification, however, the frequency was less than 50% (46.8%). To clarify the basic branching pattern of the original internal iliac artery and to simplify the classification for medical purposes , a new classification system was designed. The superior gluteal, inferior gluteal and internal pudendal arteries were defined as the major branches of the internal iliac artery, and the umbilical artery was excluded from this group. The branching of the internal iliac artery was classified into 4 groups. Almost 80% of the present specimens were included in Group A of the new classification , namely, the internal iliac artery dividing into two major branches, the superior gluteal artery and the common trunk of the inferior gluteal and internal pudendal arteries. This type of branching seemed to be the basic branching pattern for the original internal iliac artery.

The tumour epithelium was composed of several cell types demonstrating various developmental stages from the primitive clear cells to the basal cells demonstrating a tendency to differentiate toward basal cells in the apocrine transitional portion or myoepithelial lineage, or luminal cells toward the ductal or secretory epithelium. These results support the classical concept that syringocystadenoma papilliferum is a hamartomatous tumour that arises from pluripotent cells.

GABA is known to produce membrane depolarization and secretion in adrenal medullary (AM) cells in various species. However, whether the GABAergic system is intrinsic or extrinsic or both in the adrenal medulla and the role that GABA plays are controversial. Therefore, these issues were addressed by combining a biochemical and functional analysis. Glutamic acid decarboxylase (GAD), a GABA synthesizing enzyme, and vesicular GABA transporter (VGAT) were expressed in rat AM cells at the mRNA and protein levels, and the adrenal medulla had no nerve fibre-like structures immunoreactive to an anti-GAD Ab. The double staining for VGAT and chromogranin A indicates that GABA was stored in chromaffin granules. The α1, α3, β2/3, γ2 and δ subunits of GABA A receptors were identified in AM cells at the mRNA and protein levels. Pharmacological properties of GABA-induced Cl − currents, immunoprecipitation experiments and immunocytochemistry indicated the expression of not only γ2-, but also δ-containing GABA A receptors, which have higher affinities for GABA and neurosteroids. Expression of GATs, which are involved in the clearance of GABA at GABAergic synapses, were conspicuously suppressed in the adrenal medulla, compared with expression levels of GABA A receptors. Increases in Ca 2+ signal in AM cells evoked trans-synaptically by nerve stimulation were suppressed during the response to GABA, and this suppression was attributed to the shunt effect of the GABA-induced increase in conductance. Overall Ca 2+ responses to electrical stimulation and GABA in AM cells were larger or smaller than those to electrical stimulation alone, depending on the frequency of stimulation. The results indicate that GABA functions as a paracrine in rat AM cells and this function may be supported by the suppression of GAT expression and the expression of not only γ2-, but also δ-GABA A receptors.