PE38KDEL-loaded anti-HER2 nanoparticles inhibit breast tumor progression with reduced toxicity and immunogenicity

Abstract

The clinical use of Pseudomonas exotoxin A (PE)-based immunotoxins is limited by the toxicity and immunogenicity of PE. To overcome the limitations, we have developed PE38KDEL-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles conjugated with Fab' fragments of a humanized anti-HER2 monoclonal antibody (rhuMAbHER2). The PE38KDEL-loaded nanoparticles-anti-HER2 Fab' bioconjugates (PE-NP-HER) were constructed modularly with Fab' fragments of rhuMAbHER2 covalently linked to PLGA nanoparticles containing PE38KDEL. Compared with nontargeted nanoparticles that lack anti-HER2 Fab', PE-NP-HER specifically bound to and were sequentially internalized into HER2 overexpressing breast cancer cells, which result in significant cytotoxicity in vitro. In HER2 overexpressing tumor xenograft model system, administration of PE-NP-HER showed a superior efficacy in inhibiting tumor growth compared with PE-HER referring to PE38KDEL conjugated directly to rhuMAbHER2. Moreover, PE-NP-HER was well tolerated in mice with a higher LD(50) (LD(50) of 6.86 +/- 0.47 mg/kg vs. 2.21 +/- 0.32 mg/kg for PE-NP-HER vs. PE-HER (mean +/- SD); n = 3), and had no influence on the plasma level of plasma alanine aminotransferase (ALT) of animals when injected at a dose of 1 mg/kg where PE-HER caused significant increase of serum ALT in the treated mice. Notably, PE-NP-HER was of low immunogenicity in development of anti-PE38KDEL neutralizing antibodies and was less susceptible to inactivation by anti-PE38KDEL antibodies compared with PE-HER. This novel bioconjugate, PE-NP-HER, may represent a useful strategy for cancer treatment.

Functionalizing PLGA and PLGA Derivatives for Drug Delivery and Tissue Regeneration Applications

“…Breast cancer [176] Human/ mouse chimeric anti-GD2 antibody ch14.18/ CHO Letrozole Anti-GD2 antibody ch14.18/CHO was used to functionalize PLGA nanoparticles with an aromatase inhibitor (letrozole) encapsulated to target GD2-positive glioblastoma (GBM) cells. This nanosystem was coadministered with temozolomide, resulting in a higher reduction of GBM cells.…”

Polylactide-co-glycolide nanoparticles for controlled delivery of anticancer agents

“…Notably, PE-NP-HER was of low immunogenicity in the development of anti-PE38KDEL-neutralizing antibodies, and was less susceptible to inactivation by anti-PE38KDEL antibodies compared with PE-HER. 149 …”

Antibody-Targeted Nanoparticles for Cancer Treatment

“…For example, Fab fragments derived from a humanised anti-HER2 mAb have been successfully used to target pseudomonas exotoxin A (PE) encapsulated within PLGA NPs [80].…”