Skip to content

#ADC/偶联药物

Today 0 items
Oct 15Thu
  1. biorxiv.org42

    Spatial Tumour Tissue Distribution Dynamics of a Bicycle Peptide-MMAE Toxin Conjugate Profiled by Targeted Mass Spectrometry

    Laser capture microdissection coupled to targeted LC-PRM mass spectrometry maps the spatial distribution of MMAE released from the NECTIN-4-binding Bicycle Drug Conjugate zelenectide pevedotin (BT8009) at sub-tissue resolution in mice. The method showed progressive accumulation and sustained retention of MMAE in tumour tissues over 24 h, while levels in plasma, liver and muscle declined after early exposure, and revealed heterogeneous MMAE distribution between tumour cell-rich and stroma-rich regions with distinct temporal patterns.

Oct 13Tue
  1. biorxiv.org51

    Trastuzumab deruxtecan kills skin and uveal melanoma in vivo by HER2-independent payload release

    Trastuzumab deruxtecan (T-DXd) inhibited all subcutaneous melanoma PDXs and outperformed trastuzumab emtansine (T-DM1), which had limited activity, while liver models were less sensitive. Parental and ERBB2-knockout xenografts responded similarly at first, though knockout tumors regrew earlier, and melanoma cells resisted both ADCs in vitro with little trastuzumab uptake. Tumor-derived cathepsin L found outside melanoma cells suggests payload release can occur extracellularly, independent of HER2.

    Why it matters: Suggests T-DXd may work in melanoma through HER2-independent payload cleavage, widening its potential use beyond HER2-positive tumors.

Oct 10Sat
  1. biorxiv.org58

    NECTIN4 defines a subtype-dependent tumor state coupling enfortumab vedotin targetability to antitumor immunity in bladder cancer

    NECTIN4, the target of enfortumab vedotin (EV), acts as a subtype-dependent determinant of tumor state and antitumor immunity in bladder cancer. Integrating clinical multi-omics, spatial and single-cell immune profiling, and experimental models, the work shows NECTIN4-high basal/squamous muscle-invasive tumors had favorable survival, higher checkpoint inhibitor response rates, and a CD8+ T cell-inflamed microenvironment, with no comparable associations in luminal papillary tumors; NECTIN4-low models were preferentially sensitive to HDAC inhibition.

Oct 2Fri
  1. biorxiv.org59

    KRAS inhibition drives adaptive surfaceome remodeling and reveals ALPP/ALPPL2 as a targetable vulnerability in pancreatic cancer

    Quantitative temporal profiling of the global, phosphorylation, and surface proteome in PDAC shows that KRAS inhibition upregulates the cell surface protein ALPP through compensatory JAK2/STAT3 signaling. The authors developed a clinical-grade ALPP/ALPPL2-targeting antibody drug conjugate with site-specific MMAE conjugation, which showed single-agent efficacy in PDAC models and enhanced internalization and anti-tumor efficacy combined with KRAS inhibitors, pointing to a combination strategy to forestall KRASi resistance.

    Why it matters: It defines the KRASi-induced proteome and links a surface target to a clinical-grade ADC combination strategy against resistance.

  2. biorxiv.org52

    KRASG12C Inhibition Remodels the Non-Small Cell Lung Cancer Surfaceome to Uncover Targetable Vulnerabilities

    KRAS G12C inhibitors remodel the cell surface proteome of KRAS G12C-mutant lung adenocarcinoma, and folate receptor alpha (FOLR1) emerges as a therapeutically actionable target that is significantly upregulated during treatment, part of an acute cellular state transition toward epithelial identity. Quantitative temporal proteomic profiling across cell lines, tumor models, and treatment durations identified this adaptation. Combining KRASi with mirvetuximab soravtansine-gynx, a clinically approved FOLR1-targeting antibody drug conjugate, enhanced tumor cell cytotoxicity and deepened response and tumor control in cellular and in vivo models.

Sep 28Mon
Sep 2Wed
  1. Nature64

    Modular in vivo antibody-ADC click to reverse drug resistance in tumours.

    Sequentially administered antibodies and ADCs bearing trans-cyclooctene and tetrazine moieties ligate in vivo to form functional antibody-ADC click constructs, removing the dependence on a single target antigen. In preclinical models of HER2 and EGFR co-expression, including tumours with low, ultralow, negative or heterogeneous HER2 expression and tumours resistant to or ineligible for conventional HER2-directed ADCs, the approach showed improved antitumour activity over standard ADC monotherapy and over antibody plus ADC combinations. The platform requires no extensive antibody re-engineering and extends to other receptor pairs.

    Why it matters: It offers a modular route to overcoming antigen-heterogeneity-driven resistance to antibody-drug conjugates without antibody re-engineering.

Aug 31Mon
  1. Nature73

    A binding-to-release strategy for targeted anticancer drug delivery.

    A binding-to-release strategy decouples payload release from receptor endocytosis by placing an electrophile cleaved by a nucleophilic residue in the target binding pocket, implemented through phosphorus(V)-phenol exchange chemistry. A FAP-targeted SMDC built this way achieved 5.9-fold higher tumour MMAE exposure (AUC0-120 h) than an internalization-dependent FAP-SMDC, tumour-to-blood ratios 14.7- and 3.6-fold higher than FAP-ITR-SMDC and FAP-ITR-ADC, tumour-to-liver ratios 55.1- and 58.7-fold higher, and near-complete tumour regression across tumour models. The approach also extended to PD-L1 and an mRNA-display-derived FAP peptide, broadening the target scope for conjugates.

    Why it matters: It removes the endocytosis requirement that limits drug conjugates to roughly 10% of targets.

CBACBA Frontier Insights (CFI)Chinese Biopharmaceutical Association (CBA)www.cba-usa.org