Engineering a HER2-specific antibody-drug conjugate to increase lysosomal delivery and therapeutic efficacy.
Jeffrey C KangWei SunPriyanka KhareMostafa KarimiXiaoli WangYang ShenRaimund J OberE Sally WardPublished in: Nature biotechnology (2019)
We improve the potency of antibody-drug conjugates (ADCs) containing the human epidermal growth factor receptor 2 (HER2)-specific antibody pertuzumab by substantially reducing their affinity for HER2 at acidic endosomal pH relative to near neutral pH. These engineered pertuzumab variants show increased lysosomal delivery and cytotoxicity towards tumor cells expressing intermediate HER2 levels. In HER2int xenograft tumor models in mice, the variants show higher therapeutic efficacy than the parent ADC and a clinically approved HER2-specific ADC.
Keyphrases
- epidermal growth factor receptor
- tyrosine kinase
- advanced non small cell lung cancer
- copy number
- endothelial cells
- diffusion weighted
- diffusion weighted imaging
- magnetic resonance imaging
- type diabetes
- magnetic resonance
- insulin resistance
- adipose tissue
- ionic liquid
- high fat diet induced
- metastatic breast cancer
- metabolic syndrome
- drug delivery
- dna methylation
- contrast enhanced