BJC A New Generation of ADC Is Expected to Treat KRAS Mutant Pancreatic Cancer

1. BJC: A New Generation of ADC Is Expected to Treat KRAS Mutant Pancreatic Cancer Pancreatic cancer (PaCa) is the fourth leading cause of cancer-related deaths. In 2018, there were approximately 55,440 newly confirmed cases and 44,330 deaths in the United States. Due to the asymptomatic nature of cancer and the lack of specific biomarkers for detection, most patients are already at an advanced stage when diagnosed, and radical resection is no longer possible. Therefore, the prognosis of PaCa patients is very poor, with a five-year relative survival rate of only 8%. The construction of antibody-drug conjugates (ADC) presents many challenges that limit clinical progress. In particular, commonly used biological conjugation methods provide minimal control over the site where the drug is coupled to the antibody. Here, these difficulties are overcome by re-bridging the interchain disulfide of cetuximab (CTX) with pyridazinone to produce highly refined anti-epidermal growth factor receptor (EGFR) ADCs. Antibody-drug conjugate (ADC) usually refers to the coupling of small cytotoxic molecules to intact IgG molecules. It is one of the fastest-growing class of biotherapeutics and is currently considered to have the potential to improve PaCa treatment strategies. ADC antibodies can selectively target cells expressing antigens, and this targeting can greatly improve the therapeutic effect of coupled molecules, especially small molecules that are highly toxic and cannot be treated with a single drug. Synthesis of antibody-drug conjugates, image source: Nature

2. We evaluated the activity of ADC in vitro and in vivo in a KRAS mutant pancreatic cancer (PaCa) model with known CTX resistance. Computational models are used to quantitatively predict tumor response to different ADC dosing regimens. The study re-coupled the interchain disulfide of cetuximab (CTX) with pyridazinedione with auristatin to produce highly refined anti-EGFR (epidermal growth factor receptor) ADC. The researchers evaluated the activity of the ADC in a CTX-resistant KRAS mutant pancreatic cancer (PaCa) model and predicted the effect of various ADC dosing regimens on the tumor. Therapeutic effects of antibody-drug conjugates, image source: Nature The results showed that the ADC obtained by site-selective coupling of Auristatin and CTX, with an average drug : antibody ratio (DAR) of 3.9, would cause concentration and EGFR-dependent cytotoxicity at nanomolar concentrations. In the transplanted tumor

3. model, ADC can inhibit tumor growth and prolong survival without obvious signs of toxicity. Through mathematical modeling and analysis, it can be found that the key factors affecting the efficacy of ADC include the impact of tumor cell antigen density on the targeted regulation of drugs. In summary, this discovery provides new hope for the application of CTX in PaCa therapy, proving that it may be reformatted into next-generation ADCs and combined with predictive model tools to guide successful translation. On the other hand, this study also provides a new possibility for cetuximab to treat pancreatic cancer, indicating that it can form a new type of antibody-drug conjugate through rearrangement coupling. Huateng Pharma, professional pharmaceutical manufacturer in China, provides PEG derivatives to work as ADC linkers. Reference: Greene, M.K., Chen, T., Robinson, E. et al. Controlled coupling of an ultrapotent auristatin warhead to cetuximab yields a next-generation antibody-drug conjugate for EGFR-targeted therapy of KRAS mutant pancreatic cancer. Br J Cancer (11 September 2020).