Skip NavigationSkip to Content
Return Return to Search Results

A GPC2 antibody-drug conjugate is efficacious against neuroblastoma and small-cell lung cancer via binding a conformational epitope

  1. Author:
    Raman, Swetha
    Buongervino, Samantha N.
    Lane, Maria
    Zhelev, Doncho
    Zhu, Zhongyu
    Cui, Hong
    Martinez, Benjamin
    Martinez, Daniel
    Wang, Yanping
    Upton, Kristen
    Patel, Khushbu
    Rathi, Komal S.
    Navia, Carmen T.
    Harmon, Daniel B.
    Li, Yimei
    Pawel, Bruce
    Dimitrov, Dimiter S.
    Maris, John M.
    Julien, Jean-Philippe
    Bosse, Kristopher R.

  2. Author Address

    Hosp Sick Children, Res Inst, Program Mol Med, Toronto, ON M5G 0A4, Canada.Childrens Hosp Philadelphia, Ctr Childhood Canc Res, Div Oncol, Philadelphia, PA 19104 USA.Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15261 USA.NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA.Childrens Hosp Philadelphia, Dept Pathol, Philadelphia, PA 19104 USA.Childrens Hosp Philadelphia, Ctr Data Driven Discovery Biomed, Dept Biomed & Hlth Informat, Philadelphia, PA 19104 USA.Integral Mol, Philadelphia, PA 19104 USA.Univ Penn, Perelman Sch Med, Dept Biostat Epidemiol & Informat, Philadelphia, PA 19104 USA.Childrens Hosp Los Angeles, Dept Pathol & Lab Med, Los Angeles, CA 90027 USA.Univ Southern Calif, Keck Sch Med, Los Angeles, CA 90027 USA.Univ Penn, Perelman Sch Med, Dept Pediat, Philadelphia, PA 19104 USA.Univ Toronto, Dept Biochem & Immunol, Toronto, ON M5S IA8, Canada.Miltenyi Biotec Co, Lentigen Technol Inc, Gaithersburg, MD 20878 USA.Centrymed Pharmaceut Inc, Frederick, MD 21704 USA.
    1. Year: 2021
    2. Date: Jul 20
    3. Epub Date: 2021 07 21
  2. Journal: Cell reports. Medicine
  3. ELSEVIER,
    1. 2
    2. 7
  5. Type of Article: Article
  6. Article Number: 100344
  7. ISSN: 2666-3791
  1. Abstract:

    Glypican 2 (GPC2) is a MYCN-regulated, differentially expressed cell-surface oncoprotein and target for immune-based therapies in neuroblastoma. Here, we build on GPC2's immunotherapeutic attributes by finding that it is also a highly expressed, MYCN-driven oncoprotein on small-cell lung cancers (SCLCs), with significantly enriched expression in both the SCLC and neuroblastoma stem cell compartment.By solving the crystal structure of the D3-GPC2-Fab/GPC2 complex at 3.3 A resolution, we further illustrate that the GPC2-directed antibody-drug conjugate (ADC; D3-GPC2-PBD), that links a human GPC2 antibody (D3) to DNA damaging pyrrolobenzodiazepine (PBD) dimers, binds a tumor-specific, conformation-dependent epitope of the core GPC2 extracellular domain. We then show that this ADC induces durable neuroblastoma and SCLC tumor regression via induction of DNA damage, apoptosis, and bystander cell killing, notably with no signs of ADC-induced in vivo toxicity. These studies provide preclinical data to support the clinical translation of ADCs targeting GPC2.

    See More

  1. Keywords:

External Sources

  1. View Full Text
  2. DOI: 10.1016/j.xcrm.2021.100344
  3. PMID: 34337560
  4. PMCID: PMC8324494
  5. View record in Web of Science®
  6. WOS: 000677505000010

Library Notes

  1. Fiscal Year: FY2020-2021
NCI at Frederick

You are leaving a government website.

This external link provides additional information that is consistent with the intended purpose of this site. The government cannot attest to the accuracy of a non-federal site.

Linking to a non-federal site does not constitute an endorsement by this institution or any of its employees of the sponsors or the information and products presented on the site. You will be subject to the destination site's privacy policy when you follow the link.

ContinueCancel