Exogenous nitric oxide decreases brain vascular inflammation, leakage and venular resistance during Plasmodium berghei ANKA infection in mice.

BACKGROUND: Cerebral malaria (CM) is a lethal complication of Plasmodium falciparum infections. In the Plasmodium berghei ANKA (PbA) murine model, CM is associated with marked brain inflammation, increased expression of endothelial cell adhesion molecules and leukocyte and platelet accumulation in brain vessels, causing vascular occlusion and decreased blood flow, damaging the endothelium and leading to blood-brain barrier breakdown, leakage and hemorrhages. Exogenous nitric oxide (NO) administration largely prevents the syndrome. Here we evaluated whether the mechanism of action of NO in preventing murine CM is related to its anti-inflammatory properties and to protection of the endothelium. METHODS: C57Bl/6 mice infected with PbA were treated twice a day with saline or dipropylenetriamineNONOate (DPTA-NO). Endothelial cell adhesion molecule (ICAM-1, VCAM, E- and P-selectin) expression in brain tissue on day 6 of infection was assessed in both groups by western blot. For intravital microscopy studies, DPTA-NO-treated and saline-treated mice with a previously implanted closed cranial window were injected with albumin-FITC, anti-CD45-TxR and anti-CD41-FITC antibodies on day 6 of infection for quantification of albumin leakage, leukocyte and platelet adherence in pial vessels. RESULTS: PbA-infected mice treated with the NO-donor DPTA-NO showed decreased expression of ICAM-1 and P-selectin, but not VCAM-1, in the brain, compared to saline-treated mice. DPTA-NO treatment also decreased the number of adherent leukocytes and platelets in pial vessels, particularly in venules 30-50 µm in diameter, decreased inflammatory vascular resistance and prevented the occurrence of arteriolar and venular albumin leakage observed in saline-treated PbA-infected mice, as assessed by intravital microscopy. CONCLUSIONS: These results indicate that the protective effect of exogenous NO on murine CM is associated with decreased brain vascular expression of inflammatory markers resulting in attenuated endothelial junction damage and facilitating blood flow.

ARX788, a Site-specific Anti-HER2 Antibody-Drug Conjugate, Demonstrates Potent and Selective Activity in HER2-low and T-DM1-resistant Breast and Gastric Cancers.

First-generation antibody-drug conjugates (ADC) are heterogeneous mixtures that have shown clinical benefit, but generally exhibited safety issues and a narrow therapeutic window due, in part, to off-target toxicity caused by ADC instability. ARX788 is a next-generation, site-specific anti-HER2 ADC that utilizes a unique nonnatural amino acid-enabled conjugation technology and a noncleavable Amberstatin (AS269) drug-linker to generate a homogeneous ADC with a drug-to-antibody ratio of 1.9. ARX788 exhibits high serum stability in mice and a relatively long ADC half-life of 12.5 days. When compared in vitro against T-DM1 across a panel of cancer cell lines, ARX788 showed superior activity in the lower HER2-expressing cell lines and no activity in normal cardiomyocyte cells. Similarly, ARX788 significantly inhibited tumor growth, and generally outperformed T-DM1 in HER2-high and HER2-low expression xenograft models. Breast and gastric cancer patient-derived xenograft studies confirmed strong antitumor activity of ARX788 in HER2-positive and HER2-low expression tumors, as well as in a T-DM1-resistant model. The encouraging preclinical data support the further development of ARX788 for treatment of patients with HER2-positive breast and gastric cancer, including those who have developed T-DM1 resistance, and patients with HER2-low expression tumors who are currently ineligible to receive HER2-targeted therapy.