ITC-6102RO, a novel B7-H3 antibody-drug conjugate, exhibits potent therapeutic effects against B7-H3 expressing solid tumors.

BACKGROUND: The B7-H3 protein, encoded by the CD276 gene, is a member of the B7 family of proteins and a transmembrane glycoprotein. It is highly expressed in various solid tumors, such as lung and breast cancer, and has been associated with limited expression in normal tissues and poor clinical outcomes across different malignancies. Additionally, B7-H3 plays a crucial role in anticancer immune responses. Antibody-drug conjugates (ADCs) are a promising therapeutic modality, utilizing antibodies targeting tumor antigens to selectively and effectively deliver potent cytotoxic agents to tumors. METHODS: In this study, we demonstrate the potential of a novel B7-H3-targeting ADC, ITC-6102RO, for B7-H3-targeted therapy. ITC-6102RO was developed and conjugated with dHBD, a soluble derivative of pyrrolobenzodiazepine (PBD), using Ortho Hydroxy-Protected Aryl Sulfate (OHPAS) linkers with high biostability. We assessed the cytotoxicity and internalization of ITC-6102RO in B7-H3 overexpressing cell lines in vitro and evaluated its anticancer efficacy and mode of action in B7-H3 overexpressing cell-derived and patient-derived xenograft models in vivo. RESULTS: ITC-6102RO inhibited cell viability in B7-H3-positive lung and breast cancer cell lines, inducing cell cycle arrest in the S phase, DNA damage, and apoptosis in vitro. The binding activity and selectivity of ITC-6102RO with B7-H3 were comparable to those of the unconjugated anti-B7-H3 antibody. Furthermore, ITC-6102RO proved effective in B7-H3-positive JIMT-1 subcutaneously xenografted mice and exhibited a potent antitumor effect on B7-H3-positive lung cancer patient-derived xenograft (PDX) models. The mode of action, including S phase arrest and DNA damage induced by dHBD, was confirmed in JIMT-1 tumor tissues. CONCLUSIONS: Our preclinical data indicate that ITC-6102RO is a promising therapeutic agent for B7-H3-targeted therapy. Moreover, we anticipate that OHPAS linkers will serve as a valuable platform for developing novel ADCs targeting a wide range of targets.

Pharmacological Intervention Targeting FAF1 Restores Autophagic Flux for α-Synuclein Degradation in the Brain of a Parkinson's Disease Mouse Model.

α-Synuclein accumulation is implicated in the pathogenesis of neurodegenerative diseases, including Parkinson's disease (PD). Previously, we reported that Fas-associated factor 1 (FAF1), which plays a role in PD pathogenesis, potentiates α-synuclein accumulation through autophagy impairment in dopaminergic neurons. In this study, we show that KM-819, a FAF1-targeting compound, which has completed phase I clinical trials, interferes with α-synuclein accumulation in the mouse brain, as well as in human neuronal cells (SH-SY5Ys). KM-819 suppressed the accumulation of monomeric, oligomeric, and aggregated forms of α-synuclein in neuronal cells. Furthermore, KM-819 restored the turnover rate of α-synuclein in FAF1-overexpressing SH-SY5Y cells, implicating KM-819-mediated reconstitution of the α-synuclein degradative pathway. In addition, KM-819 reconstituted autophagic flux in FAF1-transfected SH-SY5Y cells, also suppressing α-synuclein-induced mitochondrial dysfunction. Moreover, oral administration of KM-819 also interfered with α-synuclein accumulation in the midbrain of mice overexpressing FAF1 via an adeno-associated virus system. Consistently, KM-819 reduced α-synuclein accumulation in both the hippocampus and the midbrain of human A53T α-synuclein transgenic mice. Collectively, these data imply that KM-819 may have therapeutic potential for patients with PD.

Clusterin stimulates the chemotactic migration of macrophages through a pertussis toxin sensitive G-protein-coupled receptor and Gßγ-dependent pathways.

Clusterin induces the expression of various chemotactic cytokines including tumor necrosis factor-α (TNF-α) in macrophages and is involved in the cell migration. According to the results of this study, clusterin induced the directional migration (chemotaxis) of macrophages based on a checkerboard analysis. The chemotactic activity of clusterin was prevented by pretreatment with pertussis toxin (PTX), indicating that the Gαi/o-protein coupled receptor (GPCR) was involved in the chemotactic response of clusterin. Clusterin-stimulated chemotaxis was abrogated in a dose-dependent manner by pretreatment with gallein (a Gßγ inhibitor), indicating the involvement of Gßγ released from the GPCR. In addition, inhibitors of phospholipase C (PLC, U73122) and phosphoinositide 3-kinase (PI3K, LY294002), the key targets of Gßγ binding and activation, suppressed chemotactic migration by clusterin. The phosphorylation of Akt induced by clusterin was blocked by pretreatment with gallein or LY294002 but not with U73122, indicating that Gßγ released from the PTX-sensitive Gi protein complex activated PLC and PI3K/Akt signaling pathways separately. The activation of cellular MAP kinases was essential in that their inhibitors blocked clusterin-induced chemotaxis, and Gßγ was required for the activation of MAP kinases because gallein reduced their phosphorylations induced by clusterin. In addition, the inflammation-induced migration of macrophages was greatly reduced in clusterin-deficient mice based on a thioglycollate-induced peritonitis model system. These results suggest that clusterin stimulates the chemotactic migration of macrophages through a PTX-sensitive GPCR and Gßγ-dependent pathways and describe a novel role of clusterin as a chemoattractant of monocytes/macrophages, suggesting that clusterin may serve as a molecular bridge between inflammation and its remodeling of related tissue by recruiting immune cells.

Positive remodeling is associated with vulnerable coronary plaque components regardless of clinical presentation: virtual histology-intravascular ultrasound analysis.

OBJECTIVE: We used virtual histology-intravascular ultrasound (VH-IVUS) to evaluate the relation between coronary artery remodeling pattern and plaque components in 1133 patients. METHODS: We divided the patients into two groups according to the remodeling pattern as positive remodeling (PR, remodeling index>1.05) (n=192) and intermediate remodeling (IR, remodeling index ≤ 1.05 and ≥ 0.95)/negative remodeling (NR, remodeling index<0.95) (n=941). VH-IVUS analysis classified the color-coded tissue into four major components: green (fibrotic, FT); yellow-green (fibro-fatty); white (dense calcium); and red (necrotic core, NC). Thin-cap fibroatheroma (TCFA) was defined as focal, NC-rich (≥ 10% of the cross-sectional area) plaques being in contact with the lumen in a plaque burden ≥ 40%. RESULTS: At the minimum lumen site, PR group had greater plaque plus media area (12.8 ± 4.9 vs. 9.9 ± 3.8mm(2), p<0.001) and greater %NC area (21.7 ± 12.3 vs. 18.2 ± 11.6%, p<0.001) and smaller %FT area (57.0 ± 14.5 vs. 59.4 ± 14.6%, p=0.037) compared with IR/NR group. PR group had greater plaque volume (188 ± 150 vs. 135 ± 130 mm(3), p<0.001) and greater %NC volume (19.1 ± 9.6 vs. 16.6 ± 9.2%, p=0.001) and smaller %FT volume (58.3 ± 11.7 vs. 60.6 ± 11.0%, p=0.009) compared with IR/NR group. PR group had more TCFA compared with IR/NR group (21% vs. 13%, p=0.006). Similar findings about plaque components were observed in terms of greater %NC volume and smaller %FT volume in PR group compared with IR/NR group in patients with both acute coronary syndrome and stable angina. CONCLUSIONS: VH-IVUS analysis demonstrates that PR was associated with more vulnerable plaque components compared with IR/NR regardless of their clinical presentation.

Relation between poststenting peristent plaque components and late stent malapposition after drug-eluting stent implantation: virtual histology-intravascular ultrasound analysis.

BACKGROUND: Impact of plaque composition on late stent malapposition (LSM) after drug-eluting stent (DES) implantation has not been evaluated. METHODS: We evaluated the relation between plaque components at poststenting peristent area (between external elastic membrane and stent areas) and LSM after DES implantation in 266 patients (314 native lesions; paclitaxel-eluting stent in 205 lesions, sirolimus-eluting stent in 66 lesions, zotarolimus-eluting stent in 32 lesions and everolimus-eluting stent in 11 lesions) in whom virtual-histology intravascular ultrasound was performed at index (poststenting) and follow-up (mean: 11.7 ± 4.8 months). RESULTS: LSM occurred in 24 patients with 30 lesions (9.6%) and there were no significant differences in the incidences of LSM among 4 DES groups [21/205 (10.2%) in paclitaxel-eluting stent, 6/66 (9.1%) in sirolimus-eluting stent, 2/32 (6.3%) in zotarolimus-eluting stent and 1/11 (9.1%) in everolimus-eluting stent, p=0.5)]. Patients with LSM were presented with more acute myocardial infarction (50% vs. 28%, p=0.026) and were more diabetics (50% vs. 30%, p=0.030) compared with those without LSM. Lesions with LSM had more poststenting peristent %necrotic core (NC) volume compared with those without LSM (25.8 ± 11.1% vs. 21.0 ± 5.7%, p<0.001). Independent predictors of LSM were poststenting peristent %NC volume [odds ratio (OR); 1.216, 95% CI; 1.053-1.405, p=0.008], acute myocardial infarction (OR; 2.897, 95% CI; 1.675-4.118, p=0.029), and diabetes mellitus (OR; 2.413, 95% CI; 1.543-3.996, p=0.038). CONCLUSIONS: Poststenting peristent NC component especially in patients with acute myocardial infarction and in those with diabetes mellitus is associated with the development of LSM after DES implantation.

Impact of tissue prolapse after stent implantation on short- and long-term clinical outcomes in patients with acute myocardial infarction: an intravascular ultrasound analysis.

BACKGROUND: We used intravascular ultrasound (IVUS) to evaluate the association of tissue prolapse (TP) with short- and long-term outcomes after stent implantation in 418 acute myocardial infarction (AMI) patients. METHODS: We evaluated the incidences of stent thrombosis, no-reflow, and long-term outcomes between patients with TP (n=142) and those without TP (n=276). RESULTS: twb.42w?>Acute and subacute stent thromboses occurred more frequently in patients with TP compared with those without TP (3.5% vs. 0.7%, p=0.035, and 4.2% vs. 0.7%, p = 0.013, respectively). TP volumes in 14 patients with stent thrombosis were significantly greater than those in 128 patients without stent thrombosis (3.3 ± 1.6 mm(3) vs. 2.6 ± 1.9 mm(3), p=0.012). No-reflow was developed more frequently in patients with TP compared with those without TP (25.4% vs. 9.8%, p < 0.001). Creatine kinase-MB and cardiac-specific troponin I were elevated more significantly after stenting in patients with TP compared with those without TP (Δ=+9.0 ± 25.2 U/l vs. -4.2 ± 41.6 U/l, p=0.001 and Δ=+10.0 ± 43.5 ng/ml vs. -1.2 ± 35.6 ng/ml, p=0.005, respectively). There were no significant differences in the incidences of cardiac death, MI, and target vessel revascularization at 1-year. Multivariate analysis showed that TP was the independent predictor of composite of acute and subacute stent thromboses [odds ratio (OR) = 4.211; 95% CI 1.198-14.805, p = 0.025] and composite of acute stent thrombosis and no-reflow (OR = 2.551; 95% CI 1.315-4.952, p = 0.006). CONCLUSIONS: TP was associated with poor short-term outcomes (more acute and subacute thromboses and no-reflow phenomenon), however it was not associated with worse long-term outcomes after stent implantation for infarct-related arteries in patients with AMI.

Relation between anemia and vulnerable coronary plaque components in patients with acute coronary syndrome: virtual histology-intravascular ultrasound analysis.

The aim of the present study was to evaluate the plaque components and the predictors of thin-cap fibroatheroma (TCFA) in anemic patients with acute coronary syndrome using virtual histology-intravascular ultrasound (VH-IVUS). Anemia was defined according to criteria of the World Health Organization, (i.e. , hemoglobin levels < 13 g/dL in men and < 12 g/dL in women) and we compared VH-IVUS findings between anemia group (171 patients, 260 lesions) and non-anemia group (569 patients, 881 lesions). Anemia group had greater % necrotic core (NC) volume (21% ± 9% vs 19% ± 9%, P = 0.001) compared with non-anemia group. Hemoglobin level correlated negatively with absolute NC volume (r = -0.235, P < 0.001) and %NC volume (r = -0.209, P < 0.001). Independent predictors of TCFA by multivariate analysis were diabetes mellitus (odds ratio [OR], 2.213; 95% confidence interval [CI], 1.403-3.612, P = 0.006), high-sensitivity C-reactive protein (OR, 1.143; 95% CI, 1.058-1.304, P = 0.012), microalbuminuria (albumin levels of 30 to 300 mg/g of creatinine) (OR, 2.124; 95% CI, 1.041-3.214, P = 0.018), and anemia (OR: 2.112; 95% CI 1.022-3.208, P = 0.028). VH-IVUS analysis demonstrates that anemia at the time of clinical presentation is associated with vulnerable plaque component in patients with acute coronary syndrome.

Relationship between microalbuminuria and vulnerable plaque components in patients with acute coronary syndrome and with diabetes mellitus. Virtual histology-intravascular ultrasound.

BACKGROUND: The purpose of the present study was to use virtual histology-intravascular ultrasound (VH-IVUS) to evaluate the relationship between microalbuminuria and plaque components in 920 patients. METHODS AND RESULTS: Patients with albumin levels <30mg/g creatinine were defined as having normoalbuminuria (n=824), and those with albumin levels 30-300mg/g as having microalbuminuria (n=96). The microalbuminuria group contained more patients with acute coronary syndrome (ACS; 72% vs. 61%, P=0.018) and more patients with diabetes (53% vs. 26%, P<0.001). In ACS patients, %necrotic core (NC) volume was significantly greater in the microalbuminuria group compared with the normoalbuminuria group (19±10% vs. 15±9%, P=0.019), but not in patients with stable angina. In ACS patients, thin-cap fibroatheroma (TCFA) was observed more frequently in the microalbuminuria group (36% vs. 18%, P=0.008), and microalbuminuria was the independent predictor of TCFA (odds ratio [OR], 1.106; 95% confidence interval [CI]: 1.025-1.144, P=0.018). In diabetic patients, %NC volume was significantly greater in the microalbuminuria group compared with the normoalbuminuria group (20±9% vs. 16±10%, P=0.017), but not in non-diabetic patients. In diabetic patients, TCFA was observed more frequently in the microalbuminuria group (38% vs. 17%, P=0.002) and microalbuminuria was the independent predictor of TCFA (OR, 1.120; 95%CI: 1.038-1.204, P=0.012). CONCLUSIONS: Microalbuminuria was associated with a higher number of vulnerable plaque components in ACS and diabetic patients. More intensive medical therapy is needed to stabilize the vulnerable plaque if microalbuminuria is observed in diabetic ACS patients.