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  • 1
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    Online Resource
    MTX-13, a Novel PTK7-Directed Antibody–Drug Conjugate with Widened Therapeutic Index Shows Sustained Tumor Regressions for a Broader Spectrum of PTK7-Positive Tumors
    American Association for Cancer Research (AACR) ; 2023
    In:  Molecular Cancer Therapeutics Vol. 22, No. 10 ( 2023-10-02), p. 1128-1143
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 22, No. 10 ( 2023-10-02), p. 1128-1143
    Abstract: Protein tyrosine kinase 7 (PTK7) is a Wnt signaling pathway protein implicated in cancer development and metastasis. When using a potent microtubule inhibitor (Aur0101), PTK7-targeting antibody–drug conjugate (ADC), h6M24-vc0101 (PF-06647020/cofetuzumab pelidotin) is efficacious only in limited tumor types with low response rates in a phase I trial. To improve patient response and to expand responding tumor types, we designed MTX-13, a PTK7-targeting ADC consisting of a novel antibody (Ab13) conjugated to eight molecules of topoisomerase I inhibitor exatecan through T1000, a novel self-immolative moiety. MTX-13 exhibited PTK7-specific cell binding, efficient internalization, and exatecan release to cause cytotoxic activity through DNA damage and apoptosis induction, and a strong bystander killing. MTX-13 displayed potent antitumor activities on cell line–derived xenograft and patient-derived xenograft models from a wide range of solid tumors, significantly outperforming h6M24-vc0101. PTK7 was shown to be an actionable target in small cell lung cancer for which MTX-13 showed complete and durable responses. With a consistent overexpression of PTK7 in squamous cell carcinomas derived from diverse anatomic sites, strong potency of MTX-13 in this group of heterogenous tumors suggested a common treatment strategy. Finally, MTX-13 inhibited tumor growth and metastasis in an orthotopic colon cancer xenograft model. MTX-13 displayed a favorable pharmacokinetic and safety profile in monkeys with the highest non-severely toxic dose (HNSTD) of ≥30 mg/kg, significantly higher than 3–5 mg/kg of HNSTD for h6M24-vc0101. The higher therapeutic index of MTX-13 bodes well for its clinical translation with the potential to expand the responding patient population beyond that of current PTK7-targeting ADCs.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-23-0164
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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    SSG: 12
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  • 2
    Online Resource
    Online Resource
    An Intelligent Shadow Play System With Multi-dimensional Interactive Perception
    Informa UK Limited ; 2023
    In:  International Journal of Human–Computer Interaction Vol. 39, No. 6 ( 2023-04-03), p. 1314-1326
    Details
    In: International Journal of Human–Computer Interaction, Informa UK Limited, Vol. 39, No. 6 ( 2023-04-03), p. 1314-1326
    Type of Medium: Online Resource
    ISSN: 1044-7318 , 1532-7590
    URL: Article
    DOI: 10.1080/10447318.2022.2062839
    Language: English
    Publisher: Informa UK Limited
    Publication Date: 2023
    detail.hit.zdb_id: 2021813-8
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  • 3
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    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
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  • 4
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    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
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    SSG: 12
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  • 5
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    Online Resource
    An array of 60,000 antibodies for proteome-scale antibody generation and target discovery
    American Association for the Advancement of Science (AAAS) ; 2020
    In:  Science Advances Vol. 6, No. 11 ( 2020-03-13)
    Details
    In: Science Advances, American Association for the Advancement of Science (AAAS), Vol. 6, No. 11 ( 2020-03-13)
    Abstract: Antibodies are essential for elucidating gene function. However, affordable technology for proteome-scale antibody generation does not exist. To address this, we developed Proteome Epitope Tag Antibody Library (PETAL) and its array. PETAL consists of 62,208 monoclonal antibodies (mAbs) against 15,199 peptides from diverse proteomes. PETAL harbors binders for a great multitude of proteins in nature due to antibody multispecificity, an intrinsic antibody feature. Distinctive combinations of 10,000 to 20,000 mAbs were found to target specific proteomes by array screening. Phenotype-specific mAb-protein pairs were found for maize and zebrafish samples. Immunofluorescence and flow cytometry mAbs for membrane proteins and chromatin immunoprecipitation–sequencing mAbs for transcription factors were identified from respective proteome-binding PETAL mAbs. Differential screening of cell surface proteomes of tumor and normal tissues identified internalizing tumor antigens for antibody-drug conjugates. By finding high-affinity mAbs at a fraction of current time and cost, PETAL enables proteome-scale antibody generation and target discovery.
    Type of Medium: Online Resource
    ISSN: 2375-2548
    URL: Article
    DOI: 10.1126/sciadv.aax2271
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2020
    detail.hit.zdb_id: 2810933-8
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  • 6
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    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
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 7
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    TJP1, a Membrane-Expressed Protein, is a Potential Therapeutic and Prognostic Target for Lung Cancer
    SAGE Publications ; 2022
    In:  Technology in Cancer Research & Treatment Vol. 21 ( 2022-01), p. 153303382211068-
    Details
    In: Technology in Cancer Research & Treatment, SAGE Publications, Vol. 21 ( 2022-01), p. 153303382211068-
    Abstract: Objective: Lung cancer is a malignant tumor with the highest mortality rate in the world. It is necessary to develop effective biomarkers for diagnosis or prognostic treatment to improve the survival rate of patients. In this prospective study, we identified a membrane-expressed protein Tight Junction Protein 1 (TJP1), which is an ideal therapeutic target for lung cancer, and demonstrated its role in invasion, migration, and proliferation of lung cancer. Methods: High-throughput monoclonal antibody microarrays were used to screen for differential expression of monoclonal antibodies (mAbs) in lung cancer and normal lung tissue. Differentially expressed antibodies were used to immunoprecipitate their cellular targets to be identified by mass spectrometry. The identified target TJP1 was knocked down to observe the effect of reduced gene expression on lung cancer cell function. Immunohistochemistry on human tumor tissues and The Cancer Genome Atlas (TCGA) database was used to explore the relationship between TJP1 expression in multiple cancer types and patient prognosis. Results: The antibody CL007473 was overexpressed in tumor tissue and its target protein was identified by mass spectrometry and immunofluorescence as TJP1, a membrane-expressed protein. Knockdown of TJP1 in lung cancer cell lines showed that reduced expression of TJP1 could inhibit the invasion and migration of lung cancer cells and inhibit the proliferation of cancer cells, suggesting that membrane-expressed protein TJP1 may be used as a therapeutic target for lung cancer. TCGA database analysis showed that TJP1 was highly expressed in pancreatic cancer (PAAD) tissues compared with normal tissues, and low expression was more beneficial to the prognosis and survival of PAAD patients. Conclusion: Membrane-expressed protein TJP1 may be a good therapeutic and prognostic target for lung cancer and has the potential to be a prognostic biomarker in pancreatic cancer.
    Type of Medium: Online Resource
    ISSN: 1533-0346 , 1533-0338
    URL: Article
    DOI: 10.1177/15330338221106855
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2022
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    detail.hit.zdb_id: 2220436-2
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  • 8
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    Application of an antibody chip for screening differentially expressed proteins during peach ripening and identification of a metabolon in the SAM cycle to generate a peach ethylene biosynthesis model
    Oxford University Press (OUP) ; 2020
    In:  Horticulture Research Vol. 7, No. 1 ( 2020-12)
    Details
    In: Horticulture Research, Oxford University Press (OUP), Vol. 7, No. 1 ( 2020-12)
    Abstract: Peach ( Prunus persica ) is a typical climacteric fruit that produces ethylene rapidly during ripening, and its fruit softens quickly. Stony hard peach cultivars, however, do not produce large amounts of ethylene, and the fruit remains firm until fully ripe, thus differing from melting flesh peach cultivars. To identify the key proteins involved in peach fruit ripening, an antibody-based proteomic analysis was conducted. A mega-monoclonal antibody (mAb) library was generated and arrayed on a chip (mAbArray) at a high density, covering ~4950 different proteins of peach. Through the screening of peach fruit proteins with the mAbArray chip, differentially expressed proteins recognized by 1587 mAbs were identified, and 33 corresponding antigens were ultimately identified by immunoprecipitation and mass spectrometry. These proteins included not only important enzymes involved in ethylene biosynthesis, such as ACO1, SAHH, SAMS, and MetE, but also novel factors such as NUDT2. Furthermore, protein–protein interaction analysis identified a metabolon containing SAHH and MetE. By combining the antibody-based proteomic data with the transcriptomic and metabolic data, a mathematical model of ethylene biosynthesis in peach was constructed. Simulation results showed that MetE is an important regulator during peach ripening, partially through interaction with SAHH.
    Type of Medium: Online Resource
    ISSN: 2662-6810 , 2052-7276
    URL: Article
    DOI: 10.1038/s41438-020-0249-9
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
    detail.hit.zdb_id: 2781828-7
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