Unique structure of ozoralizumab, a trivalent anti-TNFα NANOBODY® compound, offers the potential advantage of mitigating the risk of immune complex-induced inflammation

Biologics have become an important component of treatment strategies for a variety of diseases, but the immunogenicity of large immune complexes (ICs) and aggregates of biologics may increase risk of adverse events is a concern for biologics and it remains unclear whether large ICs consisting of intrinsic antigen and therapeutic antibodies are actually involved in acute local inflammation such as injection site reaction (ISR). Ozoralizumab is a trivalent, bispecific NANOBODY® compound that differs structurally from IgGs. Treatment with ozoralizumab has been shown to provide beneficial effects in the treatment of rheumatoid arthritis (RA) comparable to those obtained with other TNFα inhibitors. Very few ISRs (2%) have been reported after ozoralizumab administration, and the drug has been shown to have acceptable safety and tolerability. In this study, in order to elucidate the mechanism underlying the reduced incidence of ISRs associated with ozoralizumab administration, we investigated the stoichiometry of two TNFα inhibitors (ozoralizumab and adalimumab, an anti-TNFα IgG) ICs and the induction by these drugs of Fcγ receptor (FcγR)-mediated immune responses on neutrophils. Ozoralizumab-TNFα ICs are smaller than adalimumab-TNFα ICs and lack an Fc portion, thus mitigating FcγR-mediated immune responses on neutrophils. We also developed a model of anti-TNFα antibody-TNFα IC-induced subcutaneous inflammation and found that ozoralizumab-TNFα ICs do not induce any significant inflammation at injection sites. The results of our studies suggest that ozoralizumab is a promising candidate for the treatment of RA that entails a lower risk of the IC-mediated immune cell activation that leads to unwanted immune responses

Three-Component Reactions of Diazoesters, Aldehydes, and Imines Using a Dual Catalytic System Consisting of a Rhodium(II) Complex and a Lewis Acid

A dual catalytic system, dirhodium tetrapivalate/ytterbium­(III) triflate, enables the three-component reactions of α-alkyl-α-diazoesters, aromatic aldehydes, and <i>N</i>-benzylidenebenzylamine derivatives to afford the corresponding β-amino alcohols in good yields after hydrolysis of the oxazolidine cycloadducts, whereas no β-amino alcohols are obtained in the absence of ytterbium­(III) triflate. A similar dual catalytic system, dirhodium tetraacetate/ytterbium­(III) triflate, is found to be effective in accelerating the reactions of α-aryl-α-diazoesters in high yields. Furthermore, the reactions using dimethyl diazomalonate are described

p16^〈INK4a〉の免疫組織学的発現は, 良性および悪性の汗腺系腫瘍でともに高頻度に認められる

The expression of p16INK4a has been reported to be a significant marker for malignant transformation of epidermal tumors. However, little is known about sweat gland tumors. We examined the immunohistological expression of p16INK4a in benign and malignant sweat gland tumors. The ductal and acrosyringial portion of normal eccrine glands were positively stained with p16INK4a, while it was negative in the normal epidermis. Moderate to strong expression of p16INK4a was found in 16 of 17 eccrine poromas, 4 of 5 hidradenomas, 3 of 3 syringocystadenoma papilliferums, 2 of 2 mixed tumors, and 3 of 3 syringomas. The p16INK4a expression was observed focally or diffusely in4 of 4 porocarcinomas, 4 of 4 apocrine carcinomas and 12 of 17 extramammary Pagetʼs diseases. We conclude that the p16INK4a expression is not a good marker for dictating malignant transformation of sweat gland tumors.p16^<INK4a>の免疫組織学的発現は, 表皮の悪性化の指標の一つとされている. 汗腺腫瘍での検討はほとんど行われていない. 我々は, 良性および悪性汗腺腫瘍におけるp16^<INK4a>の免疫組織学的発現を検討した. 良性汗腺腫瘍では, 17例中16例のeccrine poroma, 5例中4例のhidradenoma, 3例中3例のsyringocystadenoma papilliferum, 2例中2例のmixed tumor, 3例中3例のsyringomaでp16^<INK4a>の発現を認めた. 悪性汗腺腫瘍では, 4例中4例のporocarcinoma, 4例中4例のapocrine carcinoma, 17例中12例のextramammary Pagetʼs disease でp16INK4aの発現を認めた. p16^<INK4a>の免疫組織学的発現は, 良性および悪性汗腺腫瘍でともに高頻度に認められたことから, 良性および悪性汗腺腫瘍を鑑別するマーカーには成り得ないと結論付けた

Virological characteristics correlating with SARS-CoV-2 spike protein fusogenicity

IntroductionThe severe acute respiratory syndrome coronavirus (SARS-CoV-2) spike (S) protein is essential in mediating membrane fusion of the virus with the target cells. Several reports demonstrated that SARS-CoV-2 S protein fusogenicity is reportedly closely associated with the intrinsic pathogenicity of the virus determined using hamster models. However, the association between S protein fusogenicity and other virological parameters remains elusive.MethodsIn this study, we investigated the virological parameters (e.g., S1/S2 cleavage efficiency, plaque size, pseudoviral infectivity, pseudovirus entry efficiency, and viral replication kinetics) of eleven previous variants of concern (VOCs) and variants of interest (VOIs) correlating with S protein fusogenicity.Results and discussionS protein fusogenicity was found to be strongly correlated with S1/S2 cleavage efficiency and plaque size formed by clinical isolates. However, S protein fusogenicity was less associated with pseudoviral infectivity, pseudovirus entry efficiency, and viral replication kinetics. Taken together, our results suggest that S1/S2 cleavage efficiency and plaque size could be potential indicators to predict the intrinsic pathogenicity and S protein fusogenicity of newly emerged SARS-CoV-2 variants