Search

BackgroundPatients with HER2-positive metastatic breast cancer (MBC) are at high risk of developing central nervous system (CNS) metastases. A potent and selective HER2 inhibitor with good blood-brain barrier (BBB) penetration is highly desirable.MethodsThe design and structure-activity relationship of DZD1516 was described. The potency and selectivity of DZD1516 were determined by enzymatic and cellular assays. The antitumor activity of DZD1516 monotherapy or in combination with HER2 antibody-drug conjugate was assessed in CNS and subcutaneous xenograft mouse models. A phase 1 first-in-human study evaluated the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of DZD1516 in patients with HER2+ MBC who relapsed from standard of care.ResultsDZD1516 showed good selectivity against HER2 over wild-type EGFR in vitro and potent antitumor activity in vivo. Twenty-three patients were enrolled and received DZD1516 monotherapy treatment across six dose levels (25-300 mg, twice daily). Dose-limiting toxicities were reported at 300 mg, and thus 250 mg was defined as the maximum tolerated dose. The most common adverse events included headache, vomiting, and hemoglobin decreased. No diarrhea or skin rash was observed at ≤ 250 mg. The mean Kp,uu,CSF was 2.1 for DZD1516 and 0.76 for its active metabolite DZ2678. With median seven lines of prior systemic therapy, the best antitumor efficacy in intracranial, extracranial and overall lesions was stable disease.ConclusionsDZD1516 provides positive proof of concept for an optimal HER2 inhibitor with high BBB penetration and HER2 selectivity. Further clinical evaluation of DZD1516 is warranted, with the RP2D being 250 mg BID.Clinicaltrialsgov identifier NCT04509596. Registered on August 12, 2020; Chinadrugtrial: CTR20202424 Registered on December 18, 2020.

DP303c is a HER2-targeted ADC with a cleavable linker-MMAE payload. Previous in vitro studies demonstrated that DP303c showed similar or better antitumor activity than T-DM1 in xenograft models. This was a multicenter, dose escalation and dose expansion phase 1 study in China. Eligible patients were 18-75 years old with HER2-positive advanced solid tumors who were unable to benefit from standard therapy. DP303c was administered intravenously every 3 weeks, with accelerated titration at lower dose of 0.5 mg/kg and 3 + 3 design with dose levels of 1.0, 2.0, 3.0 or 4.0 mg/kg at dose escalation part, followed by the selected dose level at dose expansion part. The primary endpoints were safety and tolerability, as well as identification of recommended phase 2 dose. As of Feb 28, 2023, 94 patients were enrolled and received DP303c (dose escalation: n = 22; dose expansion: n = 72), of whom 68 patients had breast cancer. One dose limiting toxicity (Grade 3 eye pain) was observed at 4.0 mg/kg dose, and the maximum tolerated dose was not reached. The most common treatment-related adverse events at grade 3 or higher were blurred vison (16.0%), dry eye (6.4%), and peripheral neuropathy (5.3%). No treatment-related death occurred. Overall, among 91 efficacy evaluable patients, 39 patients (42.9%) achieved an objective response. Disease control was observed in 62 patients (68.1%). In 66 efficacy evaluable patients with breast cancer, 34 patients achieved an objective response (51.5%). Disease control was achieved in 51 patients (77.3%). Median PFS was 6.4 months. On a molar basis, DP303c Cmax at 3.0 mg/kg doses was 132-folder higher than that for free MMAE. DP303c demonstrated promising anti-tumor activity with acceptable safety in patients with pre-treated advanced HER2 positive solid tumors, especially in breast cancer. Based on safety and efficacy results, 3.0 mg/kg Q3W was determined as recommended phase 2 dose for DP303c. (Trial registration: ClinicalTrials.gov Identifier: NCT04146610). [ABSTRACT FROM AUTHOR]

Chalcogenide cathodes with multi‐electron transfer characteristics are indispensable to aluminum‐ion batteries (AIBs). Nevertheless, their grievous capacity degradation and sluggish reaction kinetics remain fundamental challenges for the practical application. Herein, a Cu2S/Ni3S2 multiphase structure within the metal‐organic frame (MOF) derived carbon decoration layer (CNS@MC) is constructed to elevate the intrinsic electronic properties of chalcogenide cathode and realize high‐performance AIBs. The existence of outer carbon layer and strong orbital interaction at inner heterointerfaces eliminates the bandgap and arises more electrons at Fermi level, efficiently reducing the energy barrier for electron transfer and achieving high reactivity within cathodes. The CNS@MC also presents a strong electronic interaction with active solvent groups, which is beneficial to capture Al3+ and facilitate the three‐electron charge‐storage reactions. Experimental results demonstrate that the tailored CNS@MC cathode possesses superior redox kinetics due to the sufficient surface area and rapid Al‐ion diffusion during cycling. Meanwhile, the robust CNS@MC delivers ultra‐high electrochemical stability (131.1 mAh g−1 over 3500 cycles) with high coulombic efficiency and outstanding rate performance. This work offers new opportunities for optimizing the intrinsic properties of the chalcogenide electrodes based on MOF derivatives and heterostructure, providing novel thoughts for designing high‐performance AIBs. [ABSTRACT FROM AUTHOR]

Aqueous static zinc–iodine batteries attract tremendous attention because of their abundant reserves of iodine, nonflammable electrolyte, and facile assembly. Currently, scientific challenges for static zinc–iodine batteries include self‐discharge and sluggish kinetics. Herein, a lithiation approach for the iodine host to suppress the shuttle effect and catalyze iodine conversion is reported. Through regulating the d‐ and p‐band center and lowering the I−/I0 conversion barrier, Li+ intercalation into VS2 reinforces interaction with I3− and achieves catalytic conversion of iodine, ameliorating self‐discharge, and accelerating kinetics. Zinc–iodine batteries featuring LiVS2 as the iodine host reach a high iodine utilization, high Coulombic efficiencies, and a long cyclic lifespan. Notably, the performance enhancement mechanism is the thermodynamically favorable iodine conversion reaction, inhibition of the I3− appearance, and promotion of I3− consumption due to the Li+ insertion. The findings provide fundamental insights into tackling issues of static zinc–iodine batteries. [ABSTRACT FROM AUTHOR]

Research on aluminum batteries (ABs) is becoming a hotspot due to their low cost, high specific capacity, and high safety. However, the limited charge-storage capacity of cathodes has impeded the development of ABs. In this work, a novel modification strategy for 2D materials was applied to a MoS2 model to obtain a S–MoS2 cathode with large interlayer spacing and specific surface area, and its intrinsic energy-storage mechanisms were thoroughly studied. The experimental results verify that S–MoS2 possesses fast reaction kinetics and outstanding electrochemical energy-storage performance. Notably, the intrinsic interactions of all potential active surfaces in MoS2 with Al3+ and AlCl4− have been investigated comprehensively through DFT simulations for the first time. Compared with the (001) and interlayer surfaces, the lateral stacking (100) facet has stronger reactivity and adsorption stability. These in-depth insights gained from this work may contribute to the further design of 2D materials in a wide field. [ABSTRACT FROM AUTHOR]