GLORIA

GEOMAR Library Ocean Research Information Access

X

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
Filter
  • Chen, Caiwei  (3)
  • 1
    Online Resource
    Online Resource
    A cell surface-binding antibody atlas nominates a MUC18-directed antibody-drug conjugate for targeting melanoma
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research ( 2023-09-5)
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), ( 2023-09-5)
    Abstract: Recent advances in targeted therapy and immunotherapy have substantially improved the treatment of melanoma. However, therapeutic strategies are still needed for unresponsive or treatment-relapsed melanoma patients. To discover antibody-drug conjugate (ADC)-tractable cell surface targets for melanoma, we developed an atlas of melanoma cell surface binding antibodies (pAbs) using a proteome-scale antibody array platform (PETAL). Target identification of pAbs led to development of melanoma cell killing ADCs against LGR6, TRPM1, ASAP1, and MUC18, among others. MUC18 was overexpressed in both tumor cells and tumor-infiltrating blood vessels across major melanoma subtypes, making it a potential dual-compartment and universal melanoma therapeutic target. AMT-253, an MUC18-directed ADC based on topoisomerase I inhibitor exatecan and a self-immolative T moiety, had a higher therapeutic index compared to its microtubule inhibitor-based counterpart and favorable pharmacokinetics and tolerability in monkeys. AMT-253 exhibited MUC18-specific cytotoxicity through DNA damage and apoptosis and a strong bystander killing effect, leading to potent antitumor activities against melanoma cell line and patient-derived xenograft models. Tumor vasculature-targeting by a mouse MUC18-specific antibody-T1000-exatecan conjugate inhibited tumor growth in human melanoma xenografts. Combination therapy of AMT-253 with an anti-angiogenic agent generated higher efficacy than single agent in a mucosal melanoma model. Beyond melanoma, AMT-253 was also efficacious in a wide range of MUC18-expressing solid tumors. Efficient target/antibody discovery in combination with the T moiety-exatecan linker-payload exemplified here may facilitate discovery of new ADC to improve cancer treatment.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-23-1356
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 2
    Online Resource
    Online Resource
    Antibody–Exatecan Conjugates with a Novel Self-immolative Moiety Overcome Resistance in Colon and Lung Cancer
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Discovery Vol. 13, No. 4 ( 2023-04-03), p. 950-973
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 13, No. 4 ( 2023-04-03), p. 950-973
    Abstract: Antibody–drug conjugates (ADC) using DNA topoisomerase I inhibitor DXd/SN-38 have transformed cancer treatment, yet more effective ADCs are needed for overcoming resistance. We have designed an ADC class using a novel self-immolative T moiety for traceless conjugation and release of exatecan, a more potent topoisomerase I inhibitor with less sensitivity to multidrug resistance (MDR). Characterized by enhanced therapeutic indices, higher stability, and improved intratumoral pharmacodynamic response, antibody–T moiety–exatecan conjugates targeting HER2, HER3, and TROP2 overcome the intrinsic or treatment resistance of equivalent DXd/SN-38 ADCs in low-target-expression, large, and MDR+ tumors. T moiety–exatecan ADCs display durable antitumor activity in patient-derived xenograft and organoid models representative of unmet clinical needs, including EGFR ex19del/T790M/C797S triple-mutation lung cancer and BRAF/KRAS–TP53 double-mutant colon cancer, and show synergy with PARP/ATR inhibitor and anti–PD-1 treatment. High tolerability of the T moiety–exatecan ADC class in nonhuman primates supports its potential to expand the responding patient population and tumor types beyond current ADCs. Significance: ADCs combining a novel self-immolative moiety and topoisomerase I inhibitor exatecan as payload show deep and durable response in low-target-expressing and MDR+ tumors resistant to DXd/SN-38 ADCs without increasing toxicity. This new class of ADCs has the potential to benefit an additional patient population beyond current options. See related commentary by Gupta et al., p. 817. This article is highlighted in the In This Issue feature, p. 799
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-22-1368
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 2607892-2
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 3
    Online Resource
    Online Resource
    AMT-562, a Novel HER3-targeting Antibody–Drug Conjugate, Demonstrates a Potential to Broaden Therapeutic Opportunities for HER3-expressing Tumors
    American Association for Cancer Research (AACR) ; 2023
    In:  Molecular Cancer Therapeutics Vol. 22, No. 9 ( 2023-09-05), p. 1013-1027
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 22, No. 9 ( 2023-09-05), p. 1013-1027
    Abstract: HER3 is a unique member of the EGFR family of tyrosine kinases, which is broadly expressed in several cancers, including breast, lung, pancreatic, colorectal, gastric, prostate, and bladder cancers and is often associated with poor patient outcomes and therapeutic resistance. U3-1402/Patritumab-GGFG-DXd is the first successful HER3-targeting antibody–drug conjugate (ADC) with clinical efficacy in non–small cell lung cancer. However, over 60% of patients are nonresponsive to U3-1402 due to low target expression levels and responses tend to be in patients with higher target expression levels. U3-1402 is also ineffective in more challenging tumor types such as colorectal cancer. AMT-562 was generated by a novel anti-HER3 antibody Ab562 and a modified self-immolative PABC spacer (T800) to conjugate exatecan. Exatecan showed higher cytotoxic potency than its derivative DXd. Ab562 was selected because of its moderate affinity for minimizing potential toxicity and improving tumor penetration purposes. Both alone or in combination therapies, AMT-562 showed potent and durable antitumor response in low HER3 expression xenograft and heterogeneous patient-derived xenograft/organoid models, including digestive system and lung tumors representing of unmet needs. Combination therapies pairing AMT-562 with therapeutic antibodies, inhibitors of CHEK1, KRAS, and tyrosine kinase inhibitor showed higher synergistic efficacy than Patritumab-GGFG-DXd. Pharmacokinetic and safety profiles of AMT-562 were favorable and the highest dose lacking severe toxicity was 30 mg/kg in cynomolgus monkeys. AMT-562 has potential to be a superior HER3-targeting ADC with a higher therapeutic window that can overcome resistance to generate higher percentage and more durable responses in U3-1402–insensitive tumors.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-23-0198
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 2062135-8
    SSG: 12
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...