Therapeutic Use of Avidin Is Not Hampered by Antiavidin Antibodies in Humans

Petronzelli, Fiorella; Pelliccia, Angela; Anastasi, Anna Maria; Lindstedt, Ragnar; Manganello, Stefania; Ferrari, Liliana; Albertoni, Claudio; Leoni, Barbara; Rosi, Antonio; D'Alessio, Valeria; Deiana, Katia; Paganelli, Giovanni; Santis, Rita De

doi:10.1089/cbr.2010.0797

Cited by 41 publications

(37 citation statements)

References 31 publications

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“…Here, we used one dose of <25μM Avidin for delivering 100μM DEX to cartilage explants in low glucose medium containing 1% ITS. Therapeutic use of Avidin can elicit the production of anti-Avidin antibodies in-vivo 23,37,38 but this has been shown to have no effect on its safety or efficacy in humans 23,39 …”

Section: Discussionmentioning

confidence: 99%

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

Bajpayee

Quadir²,

Hammond³

et al. 2016

Osteoarthritis and Cartilage

111

129

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Objective Avidin exhibits ideal characteristics for targeted intra-cartilage drug delivery: its small size and optimal positive charge enable rapid penetration through full-thickness cartilage and electrostatic binding interactions that give long half-lives in-vivo. Here we conjugated Avidin with dexamethasone (DEX) and tested the hypothesis that single-dose Avidin-delivered DEX can ameliorate catabolic effects in cytokine-challenged cartilage relevant to post-traumatic OA. Methods Avidin was covalently conjugated with DEX using fast (ester) and slow, pH-sensitive release (hydrazone) linkers. DEX release kinetics from these conjugates was characterized using 3H-DEX-Avidin (scintillation counting). Cartilage explants treated with IL-1α were cultured with or without Avidin-DEX conjugates and compared to soluble DEX. Sulfated-glycosaminoglycan (sGAG) loss and biosynthesis rates were measured using DMMB assay and 35S-incorporation, respectively. Chondrocyte viability was measured using fluorescence staining. Results Ester linker released DEX from Avidin significantly faster than hydrazone under physiological buffer conditions. Single dose Avidin-DEX suppressed cytokine-induced sGAG loss over 3-weeks, rescued IL-1α-induced cell death, and restored sGAG synthesis levels without causing cytotoxicity. The two Avidin-DEX conjugates in 1:1 combination (fast:slow) had the most prominent bioactivity compared to single dose soluble-DEX, which had a shorter-lived effect and thus needed continuous replenishment throughout the culture period to ameliorate catabolic effects. Conclusion Intra-cartilage drug delivery remains inadequate as drugs rapidly clear from the joint, requiring multiple injections or sustained release of high doses in synovial fluid. A single dose of Avidin-conjugated drug enables rapid uptake and sustained delivery inside cartilage at low intratissue doses, and potentially can minimize unwanted drug exposure to other joint tissues.

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Section: Discussionmentioning

confidence: 99%

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

Bajpayee

Quadir²,

Hammond³

et al. 2016

Osteoarthritis and Cartilage

111

129

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“…Additionally, although naturally occurring human antiavidin antibodies can be present in human serum, it has been established with oncology patients that this does not hamper the safety and efficacy, rendering it suitable for therapeutic application 50. As a first step, the transporter with the optimal number of the targeting peptide, SST, for efficient cellular transportation of enzyme cargo was determined.…”

Section: Resultsmentioning

confidence: 99%

Boosting Antitumor Drug Efficacy with Chemically Engineered Multidomain Proteins

et al. 2018

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A facile chemical approach integrating supramolecular chemistry, site‐selective protein chemistry, and molecular biology is described to engineer synthetic multidomain protein therapeutics that sensitize cancer cells selectively to significantly enhance antitumor efficacy of existing chemotherapeutics. The desired bioactive entities are assembled via supramolecular interactions at the nanoscale into structurally ordered multiprotein complexes comprising a) multiple copies of the chemically modified cyclic peptide hormone somatostatin for selective targeting and internalization into human A549 lung cancer cells expressing SST‐2 receptors and b) a new cysteine mutant of the C3bot1 (C3) enzyme from Clostridium botulinum, a Rho protein inhibitor that affects and influences intracellular Rho‐mediated processes like endothelial cell migration and blood vessel formation. The multidomain protein complex, SST3‐Avi‐C3, retargets C3 enzyme into non‐small cell lung A549 cancer cells and exhibits exceptional tumor inhibition at a concentration ≈100‐fold lower than the clinically approved antibody bevacizumab (Avastin) in vivo. Notably, SST3‐Avi‐C3 increases tumor sensitivity to a conventional chemotherapeutic (doxorubicin) in vivo. These findings show that the integrated approach holds vast promise to expand the current repertoire of multidomain protein complexes and can pave the way to important new developments in the area of targeted and combination cancer therapy.

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“…For in vivo applications, the immunogenicity of the avidin/streptavidin–biotin system has to be considered, though this has not prevented the use of avidin‐based pretargeting in in vivo studies . In mouse models, high anti‐avidin antibody titers corresponding to those found in avidin‐treated oncology patients did not affect the safety and efficacy of avidin–biotin treatment, thus encouraging its applications . However, in cases where such immunogenicity is problematic, alternative coupling strategies should be considered, such as directly coupling one or more CrA molecules to the cCPE peptide.…”

Section: Discussionmentioning

confidence: 99%

A cCPE‐based xenon biosensor for magnetic resonance imaging of claudin‐expressing cells

Piontek

Witte

Rose

et al. 2017

Annals of the New York Academy of Sciences

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The majority of malignant tumors originate from epithelial cells, and many of them are characterized by an overexpression of claudins (Cldns) and their mislocalization out of tight junctions. We utilized the C-terminal claudin-binding domain of Clostridium perfringens enterotoxin (cCPE), with its high affinity to specific members of the claudin family, as the targeting unit for a claudin-sensitive cancer biosensor. To overcome the poor sensitivity of conventional relaxivity-based magnetic resonance imaging (MRI) contrast agents, we utilized the superior sensitivity of xenon Hyper-CEST biosensors. We labeled cCPE for both xenon MRI and fluorescence detection. As one readout module, we employed a cryptophane (CrA) monoacid and, as the second, a fluorescein molecule. Both were conjugated separately to a biotin molecule via a polyethyleneglycol chemical spacer and later via avidin linked to GST-cCPE. Nontransfected HEK293 cells and HEK293 cells stably expressing Cldn4-FLAG were incubated with the cCPE-based biosensor. Fluorescence-based flow cytometry and xenon MRI demonstrated binding of the biosensor specifically to Cldn4-expressing cells. This study provides proof of concept for the use of cCPE as a carrier for diagnostic contrast agents, a novel approach for potential detection of Cldn3/-4-overexpressing tumors for noninvasive early cancer detection.

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Therapeutic Use of Avidin Is Not Hampered by Antiavidin Antibodies in Humans

Cited by 41 publications

References 31 publications

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

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

Boosting Antitumor Drug Efficacy with Chemically Engineered Multidomain Proteins

A cCPE‐based xenon biosensor for magnetic resonance imaging of claudin‐expressing cells

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