Delivery of a BET protein degrader via a CEACAM6-targeted antibody-drug conjugate inhibits tumour growth in pancreatic cancer models.
Youya NakazawaMasayuki MiyanoShuntaro TsukamotoHiroyuki KogaiAkihiko YamamotoKentaro IsoSatoshi InoueYoshinobu YamaneYuki YabeHirotatsu UmiharaJunichi TaguchiTsuyoshi AkagiAtsumi YamaguchiMinaho KogaKohta ToshimitsuToshifumi HirayamaYohei MukaiAkihito MachinagaPublished in: Nature communications (2024)
Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis of all cancers. To improve PDAC therapy, we establish screening systems based on organoid and co-culture technologies and find a payload of antibody-drug conjugate (ADC), a bromodomain and extra-terminal (BET) protein degrader named EBET. We select CEACAM6/CD66c as an ADC target and developed an antibody, #84.7, with minimal reactivity to CEACAM6-expressing normal cells. EBET-conjugated #84.7 (84-EBET) has lethal effects on various PDAC organoids and bystander efficacy on CEACAM6-negative PDAC cells and cancer-associated fibroblasts. In mouse studies, a single injection of 84-EBET induces marked tumor regression in various PDAC-patient-derived xenografts, with a decrease in the inflammatory phenotype of stromal cells and without significant body weight loss. Combination with standard chemotherapy or PD-1 antibody induces more profound and sustained regression without toxicity enhancement. Our preclinical evidence demonstrates potential efficacy by delivering BET protein degrader to PDAC and its microenvironment via CEACAM6-targeted ADC.
Keyphrases
- induced apoptosis
- cancer therapy
- weight loss
- cell cycle arrest
- oxidative stress
- diffusion weighted imaging
- protein protein
- amino acid
- binding protein
- stem cells
- drug delivery
- bariatric surgery
- signaling pathway
- magnetic resonance
- squamous cell carcinoma
- photodynamic therapy
- roux en y gastric bypass
- small molecule
- pi k akt
- skeletal muscle
- extracellular matrix
- smoking cessation
- gastric bypass