Phase I trial of HuMax-IL8 (BMS-986253), an anti-IL-8 monoclonal antibody, in patients with metastatic or unresectable solid tumors

Abstract

Background HuMax-IL8 (now known as BMS-986253) is a novel, fully human monoclonal antibody that inhibits interleukin-8 (IL-8), a chemokine that promotes tumor progression, immune escape, epithelial-mesenchymal transition, and recruitment of myeloid-derived suppressor cells. Studies have demonstrated that high serum IL-8 levels correlate with poor prognosis in many malignant tumors. Preclinical studies have shown that IL-8 blockade may reduce mesenchymal features in tumor cells, making them less resistant to treatment. Methods Fifteen patients with metastatic or unresectable locally advanced solid tumors were enrolled in this 3 + 3 dose-escalation trial at four dose levels (4, 8, 16, or 32 mg/kg). HuMax-IL8 was given IV every 2 weeks, and patients were followed for safety and immune monitoring at defined intervals up to 52 weeks. Results All enrolled patients (five chordoma, four colorectal, two prostate, and one each of ovarian, papillary thyroid, chondrosarcoma, and esophageal) received at least one dose of HuMax-IL8. Eight patients had received three or more prior lines of therapy and five patients had received prior immunotherapy. Treatment-related adverse events occurred in five patients (33%), mostly grade 1. Two patients receiving the 32 mg/kg dose had grade 2 fatigue, hypophosphatemia, and hypersomnia. No dose-limiting toxicities were observed, and maximum tolerated dose was not reached. Although no objective tumor responses were observed, 11 patients (73%) had stable disease with median treatment duration of 24 weeks (range, 4–54 weeks). Serum IL-8 was significantly reduced on day 3 of HuMax-IL8 treatment compared to baseline ( p = 0.0004), with reductions in IL-8 seen at all dose levels. Conclusions HuMax-IL8 is safe and well-tolerated. Ongoing studies are evaluating the combination of IL-8 blockade and other immunotherapies. Trial registration NCTN, NCT02536469. Registered 23 August 2015, https://clinicaltrials.gov/ct2/show/NCT02536469?term=NCT02536469&rank=1 . Electronic supplementary material The online version of this article (10.1186/s40425-019-0706-x) contains supplementary material, which is available to authorized users.

Targeting Neutrophils to Treat Acute Respiratory Distress Syndrome in Coronavirus Disease

“…Moreover, IL-8 contributes to neutrophil activation and NET formation after binding to CXCR2 on neutrophils, thereby causing hyperinflammation. Interestingly, anti-IL-8 monoclonal antibody BMS-986253 (Humax IL-8), developed as an anti-tumor treatment ( Bilusic et al, 2019 ), is currently in clinical trial for COVID-19 (NCT04347226). AZD5069 ( Nicholls et al, 2015 ; Cullberg et al, 2018 ), danirixin ( Madan et al, 2019 ; Lazaar et al, 2020 ), and navarixin (SCH527123) ( Holz et al, 2010 ; Todd et al, 2016 ) are available CXCR2 inhibitors that ameliorate neutrophil activation in pulmonary diseases including bronchiectasis, virus-associated lung infection, COPD and asthma.…”

The Role of Interleukins in Colorectal Cancer

“…At the same time, their serum was tested and a decrease in IL-8 was found. This is the first trial on IL-8 blockade, and clinical trials on BMS-986253 are continuing [138]. However, the outcome was different for another drug, siltuximab, which is a monoclonal antibody with a high affinity for IL-6.…”

Discovery and characterization of a neutralizing pan-ELR+CXC chemokine monoclonal antibody

“…HuMab 10F8/HuMax IL-8/BMS-986253, a monoclonal antibody against CXCL8/IL-8, showed modest efficacy in early clinical trials. [23][24][25][26] Given the limitations of small molecules targeting the receptor(s) and antibodies targeting individual chemokines, as well as the likely substantial challenges of developing an antibody targeting two different high-turnover GPCRs present on a large population of cells, we chose to develop a pan-ELR + CXC chemokine neutralizing antibody. [27][28][29][30] Since the expression levels of the different chemokines varies across different disease states, an effective pan-ELR + CXC chemokine neutralizing antibody should neutralize all seven chemokines with high affinity.…”