2. Academic Validation
  3. Engineering CD276/B7-H3-targeted antibody-drug conjugates with enhanced cancer-eradicating capability

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

  • Cell Rep. 2023 Nov 28;42(12):113503. doi: 10.1016/j.celrep.2023.113503.
Yang Feng 1,  Jaewon Lee 1,  Liping Yang 1,  Mary Beth Hilton 2,  Karen Morris 2,  Steven Seaman 1,  Veera V Shivaji R Edupuganti 3,  Kuo-Sheng Hsu 1,  Christopher Dower 1,  Guojun Yu 1,  Daeho So 1,  Pradip Bajgain 1,  Zhongyu Zhu 4,  Dimiter S Dimitrov 4,  Nimit L Patel 5,  Christina M Robinson 6,  Simone Difilippantonio 6,  Marzena Dyba 7,  Amanda Corbel 8,  Falguni Basuli 9,  Rolf E Swenson 9,  Joseph D Kalen 5,  Sreedhar Reddy Suthe 10,  Myer Hussain 10,  James S Italia 10,  Colby A Souders 10,  Ling Gao 11,  Martin J Schnermann 3,  Brad St Croix 12
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Organic Synthesis Section, Chemical Biology Laboratory, CCR, NCI, Frederick, MD 21702, USA.
  • 4 Protein Interactions Section, Cancer and Inflammation Program, NCI, NIH, Frederick, MD 21702, USA.
  • 5 Small Animal Imaging Program, FNLCR, Leidos Biomedical Research, Inc., Frederick, MD 21702, USA.
  • 6 Animal Research Technical Support, FNLCR, Leidos Biomedical Research, Inc., Frederick, MD 21702, USA.
  • 7 Biophysics Resource in the Center for Structural Biology, NCI, NIH, Frederick, MD, USA.
  • 8 Invention Development Program, Technology Transfer Center, NCI, Frederick, MD 21701, USA.
  • 9 Chemistry and Synthesis Center, National Heart, Lung, and Blood Institute, NIH, Rockville, MD 20850, USA.
  • 10 BrickBio, Woburn, MA 01801, USA.
  • 11 Veterans Affairs Long Beach Healthcare System, Long Beach, CA 90822, USA.
  • 12 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.
PMID: 38019654 DOI: 10.1016/j.celrep.2023.113503
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.

Keywords

ADC; B7-H3; B7H3; CD276; CP: Cancer; PBD; TNBC; antibody-drug conjugate; breast cancer; m276-SL-PBD; pyrrolobenzodiazepine.

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