Cell Reports (Dec 2023)
Engineering CD276/B7-H3-targeted antibody-drug conjugates with enhanced cancer-eradicating capability
- Yang Feng,
- Jaewon Lee,
- Liping Yang,
- Mary Beth Hilton,
- Karen Morris,
- Steven Seaman,
- Veera V. Shivaji R. Edupuganti,
- Kuo-Sheng Hsu,
- Christopher Dower,
- Guojun Yu,
- Daeho So,
- Pradip Bajgain,
- Zhongyu Zhu,
- Dimiter S. Dimitrov,
- Nimit L. Patel,
- Christina M. Robinson,
- Simone Difilippantonio,
- Marzena Dyba,
- Amanda Corbel,
- Falguni Basuli,
- Rolf E. Swenson,
- Joseph D. Kalen,
- Sreedhar Reddy Suthe,
- Myer Hussain,
- James S. Italia,
- Colby A. Souders,
- Ling Gao,
- Martin J. Schnermann,
- Brad St. Croix
Affiliations
- Yang Feng
- 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
- Jaewon Lee
- 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
- Liping Yang
- 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
- Mary Beth Hilton
- 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
- Karen Morris
- 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
- Steven Seaman
- 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
- Veera V. Shivaji R. Edupuganti
- Organic Synthesis Section, Chemical Biology Laboratory, CCR, NCI, Frederick, MD 21702, USA
- Kuo-Sheng Hsu
- 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
- Christopher Dower
- 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
- Guojun Yu
- 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
- Daeho So
- 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
- Pradip Bajgain
- 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
- Zhongyu Zhu
- Protein Interactions Section, Cancer and Inflammation Program, NCI, NIH, Frederick, MD 21702, USA
- Dimiter S. Dimitrov
- Protein Interactions Section, Cancer and Inflammation Program, NCI, NIH, Frederick, MD 21702, USA
- Nimit L. Patel
- Small Animal Imaging Program, FNLCR, Leidos Biomedical Research, Inc., Frederick, MD 21702, USA
- Christina M. Robinson
- Animal Research Technical Support, FNLCR, Leidos Biomedical Research, Inc., Frederick, MD 21702, USA
- Simone Difilippantonio
- Animal Research Technical Support, FNLCR, Leidos Biomedical Research, Inc., Frederick, MD 21702, USA
- Marzena Dyba
- Biophysics Resource in the Center for Structural Biology, NCI, NIH, Frederick, MD, USA
- Amanda Corbel
- Invention Development Program, Technology Transfer Center, NCI, Frederick, MD 21701, USA
- Falguni Basuli
- Chemistry and Synthesis Center, National Heart, Lung, and Blood Institute, NIH, Rockville, MD 20850, USA
- Rolf E. Swenson
- Chemistry and Synthesis Center, National Heart, Lung, and Blood Institute, NIH, Rockville, MD 20850, USA
- Joseph D. Kalen
- Small Animal Imaging Program, FNLCR, Leidos Biomedical Research, Inc., Frederick, MD 21702, USA
- Sreedhar Reddy Suthe
- BrickBio, Woburn, MA 01801, USA
- Myer Hussain
- BrickBio, Woburn, MA 01801, USA
- James S. Italia
- BrickBio, Woburn, MA 01801, USA
- Colby A. Souders
- BrickBio, Woburn, MA 01801, USA
- Ling Gao
- Veterans Affairs Long Beach Healthcare System, Long Beach, CA 90822, USA
- Martin J. Schnermann
- Organic Synthesis Section, Chemical Biology Laboratory, CCR, NCI, Frederick, MD 21702, USA
- Brad St. Croix
- 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; Corresponding author
- Journal volume & issue
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Vol. 42,
no. 12
p. 113503
Abstract
Summary: 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.
