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Engineering CD276/B7-H3-targeted antibody-drug conjugates with enhanced cancer-eradicating capability

  1. Author:
    Feng,Yang
    Lee,Jaewon
    Yang,Liping
    Hilton,Mary
    Morris,Karen
    Seaman,Steven
    Edupuganti,Shivaji
    Hsu,Kuo-Sheng
    Dower, Christopher
    Yu,Guojun
    So,Daeho
    Bajgain,Pradip
    Zhu, Zhongyu
    Dimitrov, Dimiter S
    Patel,Nimit
    Robinson,Christina
    Difilippantonio,Simone
    Dyba,Marzena
    Corbel,Amanda
    Basuli, Falguni
    Swenson, Rolf E
    Kalen,Joseph
    Suthe, Sreedhar Reddy
    Hussain, Myer
    Italia, James S
    Souders, Colby A
    Gao, Ling
    Schnermann,Martin
    St Croix,Brad

  2. Author Address

    Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Frederick, MD 21702, USA., Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Frederick, MD 21702, USA; Basic Research Program, Frederick National Laboratory for Cancer Research (FNLCR), Leidos Biomedical Research, Inc., Frederick, MD 21702, USA., Organic Synthesis Section, Chemical Biology Laboratory, CCR, NCI, Frederick, MD 21702, USA., Protein Interactions Section, Cancer and Inflammation Program, NCI, NIH, Frederick, MD 21702, USA., Small Animal Imaging Program, FNLCR, Leidos Biomedical Research, Inc., Frederick, MD 21702, USA., Animal Research Technical Support, FNLCR, Leidos Biomedical Research, Inc., Frederick, MD 21702, USA., Biophysics Resource in the Center for Structural Biology, NCI, NIH, Frederick, MD, USA., Invention Development Program, Technology Transfer Center, NCI, Frederick, MD 21701, USA., Chemistry and Synthesis Center, National Heart, Lung, and Blood Institute, NIH, Rockville, MD 20850, USA., BrickBio, Woburn, MA 01801, USA., Veterans Affairs Long Beach Healthcare System, Long Beach, CA 90822, USA., Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Frederick, MD 21702, USA. Electronic address: stcroixb@mail.nih.gov.,
    1. Year: 2023
    2. Date: Nov 28
    3. Epub Date: 2023 11 28
  2. Journal: Cell Reports
    1. 42
    2. 12
    3. Pages: 113503
  4. Type of Article: Article
  5. Article Number: 113503
  1. Abstract:

    CD276/B7-H3 represents a promising target for cancer therapy based on widespread overexpression in both cancer cells and tumor-associated stroma. In previous preclinical studies, CD276 antibody-drug conjugates (ADCs) exploiting a talirine-type pyrrolobenzodiazepine (PBD) payload showed potent activity against various solid tumors but with a narrow therapeutic index and dosing regimen higher than that tolerated in clinical trials using other antibody-talirine conjugates. Here, we describe the development of a modified talirine PBD-based fully human CD276 ADC, called m276-SL-PBD, that is cross-species (human/mouse) reactive and can eradicate large 500-1,000-mm3 triple-negative breast cancer xenografts at doses 10- to 40-fold lower than the maximum tolerated dose. By combining CD276 targeting with judicious genetic and chemical ADC engineering, improved ADC purification, and payload sensitivity screening, these studies demonstrate that the therapeutic index of ADCs can be substantially increased, providing an advanced ADC development platform for potent and selective targeting of multiple solid tumor types. Copyright © 2023. Published by Elsevier Inc.

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External Sources

  1. View Full Text
  2. DOI: 10.1016/j.celrep.2023.113503
  3. PMID: 38019654
  4. PII : S2211-1247(23)01515-2

Library Notes

  1. Fiscal Year: FY2023-2024
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