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      Targeting CLDN18.2 by CD3 Bispecific and ADC Modalities for the Treatments of Gastric and Pancreatic Cancer

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          Abstract

          Human CLDN18.2 is highly expressed in a significant proportion of gastric and pancreatic adenocarcinomas, while normal tissue expression is limited to the epithelium of the stomach. The restricted expression makes it a potential drug target for the treatment of gastric and pancreatic adenocarcinoma, as evidenced by efforts to target CLDN18.2 via naked antibody and CAR-T modalities. Herein we describe CLDN18.2-targeting via a CD3-bispecific and an antibody drug conjugate and the characterization of these potential therapeutic molecules in efficacy and preliminary toxicity studies. Anti-hCLDN18.2 ADC, CD3-bispecific and diabody, targeting a protein sequence conserved in rat, mouse and monkey, exhibited in vitro cytotoxicity in BxPC3/hCLDN18.2 (IC 50 = 1.52, 2.03, and 0.86 nM) and KATO-III/hCLDN18.2 (IC 50 = 1.60, 0.71, and 0.07 nM) respectively and inhibited tumor growth of pancreatic and gastric patient-derived xenograft tumors. In a rat exploratory toxicity study, the ADC was tolerated up to 10 mg/kg. In a preliminary assessment of tolerability, the anti-CLDN18.2 diabody (0.34 mg/kg) did not produce obvious signs of toxicity in the stomach of NSG mice 4 weeks after dosing. Taken together, our data indicate that targeting CLDN18.2 with an ADC or bispecific modality could be a valid therapeutic approach for the treatment of gastric and pancreatic cancer.

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          Most cited references 38

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          Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries

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            Strategies and challenges for the next generation of antibody–drug conjugates

            Antibody–drug conjugate (ADCs), which aim to target highly cytotoxic drugs specifically to cancer cells, are one of the fastest growing classes of anticancer therapeutics, with more than 50 such agents currently in clinical trials. This Review discusses lessons learned and emerging strategies in the development of ADCs, including aspects such as target selection, the development of warheads, the optimization of linkers and new conjugation chemistries, and provides an overview of agents that are currently in clinical trials.
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              Gastric cancer: epidemiology, prevention, classification, and treatment

              Gastric cancer is the second most common cause of cancer-related deaths in the world, the epidemiology of which has changed within last decades. A trend of steady decline in gastric cancer incidence rates is the effect of the increased standards of hygiene, conscious nutrition, and Helicobacter pylori eradication, which together constitute primary prevention. Avoidance of gastric cancer remains a priority. However, patients with higher risk should be screened for early detection and chemoprevention. Surgical resection enhanced by standardized lymphadenectomy remains the gold standard in gastric cancer therapy. This review briefly summarizes the most important aspects of gastric cancers, which include epidemiology, risk factors, classification, diagnosis, prevention, and treatment. The paper is mostly addressed to physicians who are interested in updating the state of art concerning gastric carcinoma from easily accessible and credible source.
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                Author and article information

                Contributors
                gzhu108@live.com
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                10 June 2019
                10 June 2019
                2019
                : 9
                Affiliations
                [1 ]ISNI 0000 0000 8800 7493, GRID grid.410513.2, Pfizer Cancer Immunology Discovery, , Pfizer Worldwide Research and Development, ; 230 E. Grand Avenue, South San Francisco, CA 94080 USA
                [2 ]ISNI 0000 0000 8800 7493, GRID grid.410513.2, Drug Safety Research and Development, , Pfizer Worldwide Research and Development, ; 10646 Science Center Dr., San Diego, CA 92121 USA
                [3 ]ISNI 0000 0000 8800 7493, GRID grid.410513.2, BioMedicine Design, , Pfizer Worldwide Research and Development, ; 10646 Science Center Dr., San Diego, CA 92121 USA
                [4 ]ISNI 0000 0000 8800 7493, GRID grid.410513.2, Drug Safety Research and Development, , Pfizer Worldwide Research and Development, ; 280 Shennecossett Rd, Groton, CT 06340 USA
                [5 ]Present Address: 23 and Me, 349 Oyster Point Blvd, South San Francisco, CA 94080 USA
                [6 ]ISNI 0000 0004 0402 1634, GRID grid.418227.a, Present Address: Gilead Sciences, ; 333 Lakeside Drive, Foster City, CA 94404 USA
                [7 ]Present Address: Grifols Diagnostic Solutions, 6455 Christie Ave B-334C, Emeryville, CA 94608 USA
                [8 ]Present Address: Kodiak Sciences Inc., 2631 Hanover St, Palo Alto, CA 94304 USA
                [9 ]Present Address: Applied Molecular Transport, 1 Tower Place, Suite 850, South San Francisco, CA 94080 USA
                [10 ]Present Address: Covance Inc. Early Phase Development Solutions, 3301 Kinsman Blvd, Madison, WI 53704 USA
                [11 ]ISNI 0000 0004 0393 4335, GRID grid.418019.5, Present Address: GSK, ; 1250 South Collegeville Road, Collegeville, PA 19426 USA
                [12 ]GRID grid.504110.1, Present Address: Alector, ; 151 Oyster Point Blvd #300, South San Francisco, CA 94080 USA
                [13 ]Present Address: Allogene Therapeutics, 210 E. Grand Avenue, South San Francisco, CA 94080 USA
                [14 ]GRID grid.419971.3, Present Address: Bristol-Myers Squibb, ; 700 Bay Rd suite A, Redwood City, CA 94063 USA
                [15 ]Present Address: Multitude Therapeutics, Abmart, 3698 Haven Avenue Suite A, Redwood City, CA 94063 USA
                Article
                44874
                10.1038/s41598-019-44874-0
                6557842
                31182754
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                Funding
                Funded by: FundRef https://doi.org/10.13039/100004319, Pfizer (Pfizer Inc.);
                Funded by: All authors are current or former employees of Pfizer Inc.
                Categories
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                © The Author(s) 2019

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                gastrointestinal cancer, cancer

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