Preclinical Pharmacology and Safety of a Novel Avidin Derivative for Tissue‐Targeted Delivery of Radiolabelled Biotin

Abstract

Abstract:We recently described an oxidized avidin variant, named AvidinOX Ò , which is a product that chemically links to tissue proteins while maintaining the capacity to uptake intravenously administered biotin. Such product proved to be successful in targeting radionuclide therapy in a mouse model of inoperable breast cancer. Here, we show that the uptake of a single or multiple doses of biotin (up to five times), by the tissue-bound AvidinOX Ò , is stable for 2 weeks. Taking into account that oxidized avidin is the first chemically reactive protein to be proposed for clinical use, we evaluated its tolerability, immunogenicity and mutagenicity. Present in vitro data indicate that AvidinOX Ò (up to 10 lg ⁄ 5 · 10 5 cells) does not affect cell viability or proliferation of PC3 human prostate cancer or 3T3 mouse fibroblast cell lines as well as primary mouse spleen cells. Safety pharmacology and toxicology studies were conducted using AvidinOX Ò up to the highest concentration compatible with its solubility (about 12 mg ⁄ mL), representing four times the product concentration intended for human use, and in the maximum administrable volume compatible with each study system. The intramuscular administration in rat and monkey induced a moderate to strong inflammatory response particularly after a second administration and consistently with the induction of an immune response. Interestingly, the intramuscular administration of AvidinOX Ò to rodents and monkeys exhibiting very high anti-avidin antibody titres was well tolerated with no systemic symptoms of any kind. Intravenous administration of AvidinOX Ò , performed to mimic an accidental injection of the dose intended for a local administration (15 lL of 3.3 mg ⁄ mL solution), showed significant localization of the product into the spleen not associated with uptake of the radiolabelled biotin intravenously injected after 24 hr, thus suggesting rapid inactivation. No mutagenic activity was induced by oxidized avidin in prokaryotic and eukaryotic cells. Overall, the present data indicate that AvidinOX Ò is well tolerated in rodents and nonhuman primates, thus supporting its clinical use within protocols of radionuclide therapy of inoperable tumour lesions.Recently, a novel pre-targeted interstitial radionuclide therapy, named intraoperative avidination for radionuclide treatment (IART Ò

Charge based intra-cartilage delivery of single dose dexamethasone using Avidin nano-carriers suppresses cytokine-induced catabolism long term

“…Avidin-DEX also inhibited cytokine-induced loss of chondrocyte viability and rescued matrix biosynthesis levels. Avidin has been reported to have no adverse effects on safety in humans 23,24 and no effects on cartilage viability or biosynthesis even at high concentrations in-vitro 10 . Nevertheless, as covalent attachment of poly(ethylene glycol) (PEG) can further shield potential immunogenic responses 25 to highly cationic species, we conjugated PEG to Avidin to further ensure in-vivo compatibility.…”

AvidinOX-anchored biotinylated trastuzumab and pertuzumab induce down-modulation of ErbB2 and tumor cell death at concentrations order of magnitude lower than not-anchored antibodies

“…In the last decade, our group has been exploiting the avidin/biotin system for therapeutic approaches [1–4; 6–8; 17–24]. Currently, the oxidized version of Avidin, named AvidinOX, is being injected into inoperable liver metastases from colorectal cancer acting as a receptor for intravenously administered radioactive biotin (ClinicalTrials.gov NCT02053324).…”

Chemical Linkage to Injected Tissues Is a Distinctive Property of Oxidized Avidin

“…The use of this product for the targeted delivery of radiolabeled biotin will be clinically evaluated in the next future supported by the good safety and tolerability data obtained in rodents and non human primate studies [27].…”