The lipophilic CdSe quantum dot (QD) coated with trioctylphosphine oxide (TOPOQD) can be extracted from chloroform into water upon interaction with macrocyclic glycocluster amphiphile 1. The QD-conjugated and highly fluorescent sugar ball of a size of 15 nm (TOPOQD1) thus solubilized in water readily invades Hela cells via endocytosis. The endocytic activity of TOPOQD1 (15 nm), in light of those of the micellar homoaggregate of 1 (5 nm) and the virus-like 1-DNA conjugate (50 nm) as references, reveals a dramatic size effect (50 > 15 > 5) in the subviral size region. The optimal size at approximately 50 nm indicates that size complementarity which governs molecular recognition in small host-guest systems also plays key roles in the encapsulation of nanometric guest particles by the endocytic vesicles (=100 nm) as a macrobiomolecular host. The work thus suggests an utmost importance of size control at the viral size when designing molecular (gene, drug, probe, etc.) delivery machines.
Monoclonal antibody-based therapeutic agents (antibody drugs) have attracted considerable attention as a new type of drug. Concomitantly, the use of quantitative approaches for characterizing antibody drugs, such as liquid chromatography (LC)-mass spectrometry (MS), has increased. Generally, selective quantification of antibody drugs is done using unique peptides from variable regions (V and V) as surrogate peptides. Further, numerous internal standards (ISs) such as stable isotope-labeled (SIL)-intact proteins and SIL-surrogate peptides are used. However, developing LC-MS methodology for characterizing antibody drugs is time-consuming and costly. Therefore, LC-MS is difficult to apply for this purpose, particularly during the drug discovery stage when numerous candidates must be evaluated. Here, we demonstrate an efficient approach to developing a quantitative LC/electrospray ionization (ESI)-selected reaction monitoring (SRM)/MS method for characterizing antibody drugs. The approach consists of the following features: (i) standard peptides or SIL-IS are not required; (ii) a peptide from the homologous monoclonal antibody serves as an IS; (iii) method development is monitored using a spiked plasma sample and one quantitative MS analysis; and (iv) three predicted SRM assays are performed to optimize quantitative SRM conditions such as transition, collision energy, and declustering potential values. Using this strategy, we developed quantitative SRM methods for infliximab, alemtuzumab, and bevacizumab with sufficient precision (<20%)/accuracy (<±20%) for use in the drug discovery stage. We have also demonstrated that choosing a higher homologous peptide pair (from analyte mAb/IS mAb) is necessary to obtain the sufficient precision and accuracy. Graphical abstract ᅟ.
KRAS is one of the most frequently mutated oncogenes in various cancers. Among KRAS mutations, KRAS G12D is the most frequent driver mutation and is found in approximately 34% of patients with pancreatic ductal adenocarcinoma (PDAC), 12% of patients with colorectal cancer (CRC), 4% of patients with lung adenocarcinoma, and in a subset of patients with other solid tumors. We have identified ASP3082 as a novel KRAS G12D degrader with high potency and selectivity. Here, we have evaluated in vivo antitumor activities and pharmacodynamic properties of ASP3082 in various KRAS G12D-mutated xenograft models. ASP3082 was intravenously administered to KRAS G12D-mutated cancer-xenograft-bearing mice, and plasma and tumors were collected at defined time points. The drug concentration and KRAS-related signal transduction were measured in the xenograft model. The in vivo efficacy of ASP3082 monotherapy was confirmed in multiple xenograft mouse models following intravenous administration. Once-weekly intravenous administration of ASP3082 induced dose-dependent and significant growth inhibition of KRAS G12D PDAC tumors, resulting in profound tumor regression without body weight loss. ASP3082 showed sustained concentrations in the xenograft tumors after a single intravenous administration and decreased KRAS G12D-mutated-protein levels according to the duration of the sustained ASP3082 concentrations. ASP3082 also demonstrated marked inhibition of extracellular signal-regulated kinase phosphorylation and its downstream genes, and potently induced cleavage of caspase 3. In addition, ASP3082 exhibited potent antitumor activities in not only PDAC but also CRC and non-small cell lung cancer KRAS G12D-mutated mouse models. These studies demonstrated that ASP3082 induced degradation of KRAS G12D protein, inhibition of KRAS downstream molecules, and an apoptotic response to show dose-dependent antitumor activity in multiple KRAS G12D-mutated cancer models. ASP3082 is a potential therapeutic agent for patients with tumors harboring the KRAS G12D mutation. Currently, a phase 1 clinical trial is underway in patients with previously treated, locally advanced or metastatic solid tumors with KRAS G12D mutation (NCT05382559). Citation Format: Takeyuki Nagashima, Tomohiro Yoshinari, Yoshihiro Nishizono, Mamoru Tasaki, Kohei Inamura, Hiroki Ishioka, Atsushi Suzuki, Fumio Osaki, Yosuke Yamanaka, Masahiko Hayakawa. Novel KRAS G12D degrader ASP3082 demonstrates in vivo, dose-dependent KRAS degradation, KRAS pathway inhibition, and antitumor efficacy in multiple KRAS G12D-mutated cancer models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5735.
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