No abstract

Background: ERBB2 is a proto-oncogene of multiple cancers including breast and gastric cancers with HER2 protein overexpression or gene amplification and has been proven clinically as a valid target for these cancers. HER2-targeting agents such as Herceptin®, Kadcyla® and ENHERTU® have been approved by the FDA for the treatment of breast cancer, but these drugs still face the challenge of acquired resistance and/or severe adverse reactions in clinical use. Therefore, there is significant unmet medical need for developing new agents that are more effective and safer for patients with advanced HER2-positive solid tumors including breast and gastric cancers. Methods: We report here the making of MRG002, a novel HER2-targeted ADC, and preclinical characterization including pharmacology, pharmacodynamics and toxicology and discuss its potential as a novel agent for treating patients with HER2-positive solid tumors. Results: MRG002 exhibited similar antigen binding affinity but much reduced ADCC activity compared to trastuzumab. In addition to potent in vitro cytotoxicity, MRG002 showed tumor regression in both high- and medium-to-low HER2 expressing in vivo xenograft models. Furthermore, MRG002 showed enhanced antitumor activity when used in combination with an anti-PD-1 antibody. Main findings from GLP-compliant toxicity studies are related to the payload and are consistent with literature report of other ADCs with MMAE. Conclusion: MRG002 has demonstrated a favorable toxicity profile and potent antitumor activities in the breast and gastric PDX models with varying levels of HER2 expression, and/or resistance to trastuzumab or T-DM1. A phase I clinical study of MRG002 in patients with HER2-positive solid tumors is ongoing (CTR20181778).

No abstract

High-temperature titanium matrix composites reinforced with hybrid reinforcements are synthesized by common casting and hot working technologies. Tensile properties are tested at different temperatures and strain rates. Ultimate strengths of the composites are significantly enhanced under all conditions and decrease when the strain rate is lower. Equicohesive temperature of the matrix is around 873 K at the strain rate 10−3s−1 and well below 873 K at 10−5s−1. At higher temperature or lower strain rate, interfacial debonding is more drastic and reduces the strengths of composites. The materials are embrittled under creep-rupture conditions. Strict reinforcement morphology is required for more complex service conditions at high temperatures in metal matrix composites.

No abstract

No abstract

No abstract

No abstract