Search

Current clinical HER2-targeting ADCs, especially T-DXd, have shown strong efficacy in HER2-expressing/mutant cancers, however, with adverse events such as hematologic toxicities and interstitial lung disease (ILD)/pneumonitis. Here we presented a potential best-in-class HER2-directed ADC, SHR-A1811, which was composed of trastuzumab, a stable and cleavable linker, and a novel topoisomerase I inhibitor payload (SHR9265). SHR9265 was a delicately selected exatecan derivative with a better liposolubility and cellular permeability: SHR9265 had a higher AlogP value than SHR7971, synthesized using published DXd structure (3.67 vs. 2.72). Consistently, SHR9265 showed ~5 times higher membrane permeability (PAMPA model) at pH5 and pH7.4. Cell killing activity of SHR9265 was ~3 times more potent than SHR7971. SHR-A1811 had a drug-to-antibody ratio (DAR) of 5.7, and showed HER2-dependent growth inhibition against various breast cancer and gastric cancer cell lines. In the bystander killing system, SHR-A1811 was able to kill both SK-BR-3 (HER2+) and MDA-MB-468 (HER2-) cells when co-cultured, with the IC50 on MDA-MB-468 of 0.28 nM. The in vitro efficacy of SHR-A1811 was comparable with anti-Her2-SHR9265 (DAR 7.5) and ADC1 (synthesized using T-DXd structure), and stronger than anti-Her2-SHR9265 (DAR 3.5). In SK-BR-3 (HER2 high), JIMT-1 (HER2 moderate) and capan-1 (HER2 low) xenograft models, SHR-A1811 treatment resulted in a dramatic and sustained inhibition of tumor growth. A significantly stronger antitumor activity was observed for SHR-A1811 than ADC1 under the same dosages. Moreover, SHR-A1811 showed good stability and improved safety profiles, presumably due to the proper steric hindrance which was purposely designed on the payload (SHR9265). Less than 2% of payload release was observed in human plasma after a 21-day incubation. The HNSTD of SHR-A1811 in cynomolgus monkeys was 40mpk with thymus as the main target organ. No death and lung lesions were observed at dose levels up to 70mpk for 42 days, while ADC1 led to one male cynomolgus monkey death on day 10 at 70mpk with multiple lung damages. These findings were consistent with safety profiles observed in a multi-center, dose-escalation phase I clinical trial (NCT0444620). Patients with different solid tumor types received initial intravenous doses of SHR-A1811 from 1 to 8.0 mg/kg. Only trace amount of free toxin was detected. The Cmax of payload was 3.85 ng/ml at 8mg/kg of SHR-A1811. The incidence of G2 ILD was < 2.5% and the treatment discontinuation rate was 5.1% across doses. In summary, with a highly permeable payload, optimized DAR, great potency and better clinical safety profiles, SHR-A1811 has demonstrated the best-in-class potential. Currently SHR-A1811 has entered phase II and phase III clinical studies for breast cancer, gastric cancer, colorectal cancer, and NSCLC (NCT05424835, NCT05482568, NCT04818333, NCT05349409). Citation Format: Ting Zhang, Lingfeng You, Jianyan Xu, Junzhao Yin, Bolei Qu, Yuchang Mao, Beibei Fu, Dan Cao, Linda Zhao, Jun Feng, Min Hu, Feng He. SHR-A1811, a novel anti-HER2 ADC with superior bystander effect, optimal DAR and favorable safety profiles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB031.

Trop-2 is a promising target for ADC therapy due to its high expression in many solid tumors. The approval of Trodelvy, a Trop-2 directed ADC, for the treatment of refractory or drug-resistant triple negative breast cancer (TNBC) demonstrated the therapeutic value of Trop-2-targeted ADC. However, a Boxed Warning for severe or life-threatening neutropenia and severe diarrhea suggests the safety of Trodelvy needs to be improved. Here, we presented a novel Trop2-directed ADC, SHR-A1921, consisting of a topoisomerase I inhibitor (Proprietary payload, SHR9265) conjugated to a proprietary IgG1 mAb via cleavable linkers. SHR-A1921 demonstrated several advantages over other Trop-2 directed ADCs in the field. SHR9265 is a novel exatecan derivative designed by Hengrui with a better liposolubility and cellular permeability. SHR-A1921 had a drug-to-antibody ratio (DAR) of 4. Compared with other Trop-2-targeted ADCs in the field, such as Trodelvy, TINA-SHR79711 (a molecule synthesized using the published structure of DS-1062), and SKB264, SHR-A1921 has considerable advantages as follows: (1) Stronger binding affinity to both human and rhesus macaque TROP-2 than TINA-SHR79711; (2) Improved plasma stability in plasma of different species presumably due to the proper steric hindrance which was purposely designed on the payload for reducing non-intended cleavage; (3) Stronger bystander cell killing effect presumably due to the increased lipophilicity of the payload vs. that of the payload in TINA-SHR79711; (4) Superior in vivo efficacy in a PSCC2 CDX Model (FaDu) with high Trop-2 expression (TGI 101% vs 53% [TINA-SHR79711] @ 1 mpk) and in an ovarian cancer CDX Model (SK-OV-3) with moderate Trop-2 expression (TGI 63% vs. 23% [TINA-SHR79711] @ 3 mpk; 87% vs. 16% [TINA-SHR79711] @ 10 mpk); (5) ≥ 2X longer half-life in patients# vs. SKB264 vs. IMMU-132, supporting more flexible dosing frequency; (6) Lower free toxin/ADC ratio# regarding PK exposure in patients compared with SKB264 (< 1% vs. 5-6%); (7) approximately linear pharmacokinetics profile in patients with T1/2 ranging from 2.5 to 4.5 days. In summary, SHR-A1921 is a novel anti-TROP2-targeted ADC with a high permeable payload and optimized DAR demonstrating great stability and high potency in both in vitro and in vivo studies. SHR-A1921 also showed compelling efficacy and good safety profile from 50+ subjects of Phase I clinical trial in China (NCT05154604). Pivotal phase III trial for NSCLC is planned in China. (Notes: 1. TINA-SHR7971 is a molecule that Hengrui synthesized using the published structure of DS-1062. 2. PSCC: pharyngeal squamous cell carcinoma. #. non-head-to-head comparison.) Citation Format: Ning He, Chunpeng Yang, Yang Yang, Zhendong Xue, Jianyan Xu, Linda Zhao, Jun Feng, Xin Ye, Zhe Zhang, Feng He. SHR-A1921, a novel TROP-2 ADC with an optimized design and well-balanced profile between efficacy and safety [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB030.

Co30Cr8W1.6C3Ni1.4Si coatings were fabricated on Ti6Al4V alloy using a laser thermal spraying (LTS). The surface and cross-section morphologies, phases and bonding strength of obtained coatings were investigated using scanning electronic microscopy (SEM), X-ray diffraction (XRD), and scratch test, respectively. The effects of laser power on the coefficients of friction (COFs) and corrosive-wear behaviors of Co30Cr8W1.6C3Ni1.4Si coatings were investigated using a wear tester in 3.5% NaCl solution, and the electrochemical corrosion performance was analyzed using an electrochemical workstation. The experimental results show that the Co30Cr8W1.6C3Ni1.4Si coating is bonded with the substrate in the metallurgical form, and the bonding strengths of Co30Cr8W1.6C3Ni1.4Si coatings fabricated at the laser power of 1 000, 1 200, and 1 400 W are 76.5, 56.5, and 55.6 N, respectively. The average COFs of Co30Cr8W1.6C3Ni1.4Si coatings fabricated at the laser power of 1 000, 1 200, and 1 400 W are 0.769, 0.893, and 0.941, respectively; and the corresponding wear rates are 0.267 × 105, 0.3 1 78 × 105, and 0.325 × 105 µm /Nm, respectively, which increases with the increase of laser power, the wear mechanism is primarily abrasive wear. The corrosion potential of Co30Cr8W1.6C3Ni1.4Si coatings fabricated at the laser power of 1 000, 1 200, and 1 400 W is −0.05, −0.25, and −0.31 V, respectively, higher than −0.45 V of substrate which enhances the electrochemical corrosion resistance of substrate.

HfC and HfTaC2 coatings with gradient composition manufactured by double-cathode glow discharge plasma surface metallurgy technology were designed to improve the wear resistance of TA15 titanium alloy. The deposition mechanism of plasma and diffusion mechanism of atoms were investigated, and the growth process of coatings was revealed. The mechanical properties comprising microhardness and elastic modulus were investigated via first-principles calculations and experimental verification. The results reveal that the wear resistance of HfC and HfTaC2 coatings with abrasive wear mechanism is always better than that of the substrate with abrasive wear, adhesive wear and oxidation wear mechanism. The volume wear rates of the coatings are reduced by 90%–97% compared with the substrate, and that of HfTaC2 coatings are reduced by 29.9%–45.5% compared with HfC coatings. Furthermore, V-shaped cross section profiles of wear scars formed on HfC coatings, and U-shaped on HfTaC2 coatings, which is attributed to the addition of tantalum which causes HfC to form a sufficient solid solution, a 0.187–0.030 Å elongation of Ta-C bond length and 0.039–0.051 Å shortening of Hf-C bond length led to the unit cell shrinkage and the Bragg lattice changes from face-centered cubic to face-centered square lattice; accordingly, hardness and wear behavior were further improved.

A convergent and stereoselective total synthesis of the previously assigned structure of azaspiracid-3 has been achieved by a late-stage Nozaki-Hiyama-Kishi coupling to form the C21-C22 bond with the C20 configuration unambiguously established from l-(+)-tartaric acid. Postcoupling steps involved oxidation to an ynone, modified Stryker reduction of the alkyne, global deprotection, and oxidation of the resulting C1 primary alcohol to the carboxylic acid. The synthetic product matched naturally occurring azaspiracid-3 by mass spectrometry, but differed both chromatographically and spectroscopically.

A convergent and stereoselective total synthesis of the previously assigned structure of azaspiracid-3 has been achieved by a late-stage Nozaki-Hiyama-Kishi coupling to form the C21-C22 bond with the C20 configuration unambiguously established from l-(+)-tartaric acid. Postcoupling steps involved oxidation to an ynone, modified Stryker reduction of the alkyne, global deprotection, and oxidation of the resulting C1 primary alcohol to the carboxylic acid. The synthetic product matched naturally occurring azaspiracid-3 by mass spectrometry, but differed both chromatographically and spectroscopically.

BACKGROUND: Polyacrylonitrile (PAN) artificial muscles have attracted considerable attention for their fast responses. This research work is based on the preparation of novel pH-sensitive hydrogel fibers derived from hydrolyzed PAN and gelatin by wet spinning and chemical modification. RESULTS: Through characterization of the fiber dynamic and static pH-sensitive behavior, pH response times were found to improve greatly with increasing gelatin content. At a weight ratio of 3 to 7 (PAN:gelatin), the best response times were obtained at 0.59 s for elongation and 1.14 s for contraction. Study of the chemical structures of hydrolyzed PAN and gelatin, as well as the surface morphology of the hydrogel fibers, indicated that the mechanism of formation of hydrogel fibers is closely interconnected with their pH-sensitive behavior. From the standpoint of the mechanism we also found that the addition of urea gave rise to hydrogel fibers with a controllable morphology, influenced by the pH-sensitive behavior. CONCLUSION: The hydrogel system reported here is simple in preparation, but quite complex in chemical structure. The strong response of the fibers to pH provides some idea on the development of new artificial muscle systems. Copyright © 2008 Society of Chemical Industry

Azaspiracids (AZAs) are a group of biotoxins that cause food poisoning in humans. These toxins are produced by small marine dinoflagellates such as Azadinium spinosum and accumulate in shellfish. Ovine polyclonal antibodies were produced and used to develop an ELISA for quantitating AZAs in shellfish, algal cells, and culture supernatants. Immunizing antigens were prepared from synthetic fragments of the constant region of AZAs, while plate coating antigen was prepared from AZA-1. The ELISA provides a sensitive and rapid analytical method for screening large numbers of samples. It has a working range of 0.45-8.6 ng/mL and a limit of quantitation for total AZAs in whole shellfish at 57 μg/kg, well below the maximum permitted level set by the European Commission. The ELISA has good cross-reactivity to AZA-1-10, -33, and -34 and 37-epi-AZA-1. Naturally contaminated Irish mussels gave similar results whether they were cooked or uncooked, indicating that the ELISA also detects 22-carboxy-AZA metabolites (e.g., AZA-17 and AZA-19). ELISA results showed excellent correlation with LC-MS/MS analysis, both for mussel extract spiked with AZA-1 and for naturally contaminated Irish mussels. The assay is therefore well suited to screening for AZAs in shellfish samples intended for human consumption, as well as for studies on AZA metabolism.

The azaspiracid natural products display a common spiroaminal-containing terminal domain that has inspired the development of two new methods for spiroaminal syntheses—a Staudinger reduction–aza-Wittig process and a double intramolecular hetero-Michael addition. These effective laboratory approaches proceed through imine and enamine intermediates that may reflect transient biogenetic species.

A new isotactic, perfectly alternating polymer of (S)-lactic acid and oxetane was synthesized by the entropically driven ring-opening polymerization of a 14-membered cyclic diester (S,S-3) mediated by a zinc alkoxide catalyst. The polymer (S,S-PMOD) was characterized by NMR spectroscopy, size exclusion chromatography, and matrix-assisted laser desorption ionization mass spectrometry. Under polymerization conditions the equilibrium concentration (0.17 ( 0.05 M) of the monomer in toluene was essentially independent of temperature, and the average thermodynamic parameters for the ring-opening polymerization were found to be ¢Hp° ) 0.2 ( 0.7 kJ mol-1 and ¢Sp° )+ 16 ( 2 J mol-1 K-1 (standard state (S,S-3) ) 1.0 M). Theoretical calculations of the standard state enthalpy (¢Hp°) for ring-opening polymerization of various oxocyclics, including S,S-3, were well-correlated with experimental values. Kinetic studies showed that the polymerization of S,S-3 was slower (kp ) 0.82 ( 0.04 M -1 s -1 and kdp ) 0.12 ( 0.04 s -1 at 25 °C) than that of lactide (kp ) 2.2 M -1 s -1 ) using the same zinc alkoxide catalyst. Differential scanning calorimetry of S,S-PMOD showed a glass transition temperature of -30 °C for samples with molecular weights between 5 and 72 kg mol -1 . In support of the potential utility of S,S- PMOD as a PLA plasticizer, the complete miscibility of the polymeric components was demonstrated by the observation of single Tg values for a series of blends of S,S-PMOD and atactic PLA.