Recombinant immunotoxins with albumin-binding domains have long half-lives and high antitumor activity.
Junxia WeiTapan K BeraXiu Fen LiuQi ZhouMasanori OndaMitchell HoChin-Hsien TaiIra PastanPublished in: Proceedings of the National Academy of Sciences of the United States of America (2018)
Recombinant immunotoxins (RITs) are chimeric proteins consisting of a Fv that binds to a cancer cell and a portion of a protein toxin. One of these, Moxetumomab pasudotox, was shown to be effective in treating patients with some leukemias, where the cells are readily accessible to the RIT. However, their short half-life limits their efficacy in solid tumors, because penetration into the tumors is slow. Albumin and agents bound to albumin have a long half-life in the circulation. To increase the time tumor cells are exposed to RITs, we have produced and evaluated variants that contain either an albumin-binding domain (ABD) from Streptococcus or single-domain antibodies from Llama. We have inserted these ABDs into RITs targeting mesothelin, between the Fv and the furin cleavage site. We find that these proteins can be produced in large amounts, are very cytotoxic to mesothelin-expressing cancer cell lines, and have a high affinity for human or mouse serum albumin. In mice, the RIT containing an ABD from Streptococcus has a longer half-life and higher antitumor activity than the other two. Its half-life in the circulation of mice ranges from 113 to 194 min compared with 13 min for an RIT with no ABD. Cell uptake studies show the RIT enters the target cell bound to serum albumin. We conclude that RITs with improved half-lives and antitumor activity should be evaluated for the treatment of cancer in humans.
Keyphrases
- cell therapy
- papillary thyroid
- single cell
- escherichia coli
- endothelial cells
- biofilm formation
- induced apoptosis
- stem cells
- candida albicans
- dna binding
- cystic fibrosis
- mesenchymal stem cells
- adipose tissue
- dna methylation
- oxidative stress
- squamous cell carcinoma
- combination therapy
- bone marrow
- pseudomonas aeruginosa
- cell death
- cell cycle arrest
- wild type
- insulin resistance
- young adults
- genome wide
- anti inflammatory