Tolerogenic nanoparticles restore the antitumor activity of recombinant immunotoxins by mitigating immunogenicity

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 115; no. 4; pp. E733 - E742
• Main Authors: Mazor, Ronit, King, Emily M., Onda, Masanori, Cuburu, Nicolas, Addissie, Selamawit, Crown, Devorah, Liu, Xiu-Fen, Kishimoto, Takashi Kei, Pastan, Ira
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 23.01.2018
• Series: PNAS Plus
• Subjects: Animals; Antibodies, Neutralizing; Anticancer properties; Antitumor activity; Biological Sciences; Cancer; Dendritic cells; GPI-Linked Proteins - immunology; Humans; Immune checkpoint; Immunity; Immunogenicity; Immunological tolerance; Immunomodulation; Immunoregulation; Immunosuppressive agents; Immunosuppressive Agents - administration & dosage; Immunotoxins; Immunotoxins - administration & dosage; Immunotoxins - immunology; Leukemia; Leukemia - therapy; Lymphocytes; Lymphocytes T; Macrophages; Mesothelin; Monoclonal antibodies; Nanoparticles; Patients; PNAS Plus; Proteins; Rapamycin; Restoration; Rodents; Sirolimus - administration & dosage; Spleen; T cell receptors; Time Factors; Toxins; nanoparticle; cancer; antidrug antibodies; mesothelin; rapamycin
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1717063115

Protein-based drugs are very active in treating cancer, but their efficacy can be limited by the formation of neutralizing antidrug antibodies (ADAs). Recombinant immunotoxins are proteins that are very effective in patients with leukemia, where immunity is suppressed, but induce ADAs,which compromise their activity, in patients with intact immunity. Here we induced a specific, durable, and transferable immune tolerance to recombinant immunotoxins by combining them with nanoparticles containing rapamycin (SVP-R). SVP-R mitigated the formation of inhibitory ADAs in naïve and sensitized mice, resulting in restoration of antitumor activity. The immune tolerance is mediated by colocalization of the SVP-R and immunotoxin to dendritic cells and macrophages in the spleen and is abrogated by depletion of regulatory T cells. Tolerance induced by SVPs was not blocked by checkpoint inhibitors or costimulatory agonist monoclonal antibodies that by themselves enhance ADA formation.