Potentiating cancer immunotherapies with modular albumin-hitchhiking nanobody–STING agonist conjugates

The enhancement of antitumour immunity via agonists of the stimulator of interferon genes (STING) pathway is limited by pharmacological barriers. Here we show that the covalent conjugation of a STING agonist to anti-albumin nanobodies via site-selective bioconjugation chemistries prolongs the circulation of the agonist in the blood and increases its accumulation in tumour tissue, stimulating innate immune programmes that increased the infiltration of activated natural killer cells and T cells, which potently inhibited the growth of mouse tumours. The technology is modular, as demonstrated by the recombinant integration of a second nanobody domain targeting programmed death-ligand 1 (PD-L1), which further…

• NS
  National Science Foundation

  Awards: CBET-1554623, DMR 1852157, 193793
• UD
  U.S. Department of Veterans Affairs

  Award: IK6B005225
• PR
  Pharmaceutical Research and Manufacturers of America Foundation
• SG
  Susan G. Komen

  Award: CCR19609205
• NC
  National Cancer Institute

  Awards: R01 CA217987, T32CA009592, R01 CA266767, SPORE 2P50CA098131–17, R01 CA274675, K00 CA253718, F32 CA288044, R01 CA11601, R01 CA245134, P30 CA68485
• NI
  National Institute of General Medical Sciences

  Awards: T32GM065086, T32GM007347
• NI
  National Institute of Diabetes and Digestive and Kidney Diseases

  Award: T32DK101003
• CD
  Congressionally Directed Medical Research Programs

  Award: BC170037