High activity and low toxicity of a novel CD71-targeting nanotherapeutic named The-0504 on preclinical models of several human aggressive tumors

Abstract

Background Ferritin receptor (CD71) is an example of a very attractive cancer target, since it is highly expressed in virtually all tumor types, including metastatic loci. However, this target can be considered to be inaccessible to conventional target therapies, due to its presence in many healthy tissues. Here, we describe the preclinical evaluation of a tumor proteases-activatable human ferritin (HFt)-based drug carrier (The-0504) that is able to selectively deliver the wide-spectrum topoisomerase I inhibitor Genz-644282 to CD71-expressing tumors, preventing the limiting toxic effects associated with CD71-targeting therapies. Methods CD71 expression was evaluated using flow cytometry and immunohistochemistry techniques. The-0504 antiproliferative activity towards several cancer cell lines was assessed in vitro. The-0504 antitumor efficacy and survival benefit were evaluated in different human tumors, which had been grown either as xenografts or patient-derived xenografts in mice. The-0504 toxicology profile was investigated in multiple-cycle repeat-dose study in rodents. Results In vitro studies indicate that The-0504 is highly specific for CD71 expressing cells, and that there is a relationship between CD71 levels and The-0504 anticancer activity. In vivo treatments with The-0504 showed a remarkable efficacy, eradicating several human tumors of very diverse and aggressive histotypes, such as pancreas, liver and colorectal carcinomas, and triple-negative breast cancer. Conclusions Durable disease-free survival, persistent antitumor responses after discontinuation of treatment and favorable toxicology profile make The-0504 an ideal candidate for clinical development as a novel, CD71-targeted, low-toxicity alternative to chemotherapy.

Bioengineered Ferritin Nanocarriers for Cancer Therapy

“…When it enters the tumor microenvironment, MMP makes the MMP-cleavable peptide fragments, so that PASE polypeptide is detached from the surface of ferritin and the ferritin activity is restored. Then, the treatment in vivo showed significant efficacy, eradicating several highly aggressive human tumors, such as pancreatic, triple-negative breast and liver cancer [34,35].…”

“…When it enters t tumor microenvironment, MMP makes the MMP-cleavable peptide fragments, so th PASE polypeptide is detached from the surface of ferritin and the ferritin activity is stored. Then, the treatment in vivo showed significant efficacy, eradicating several high aggressive human tumors, such as pancreatic, triple-negative breast and liver canc [34,35]. In order to enhance the targeting ability of ferritin, peptides have been developed target receptors specifically expressed on the surface of different types of tumor cells.…”

Tissue-resident macrophages promote early dissemination of multiple myeloma via IL-6 and TNFα

“…We validated that the ligand-receptor pair VCAM-1:VLA-4 was upregulated on TAMs and MM cells as well as some other MM surface receptors (CD71, CD324) (Figure 7E). Targeting some of these factors such as VEGFA, 37 FGF2, 38 and TFRC 39 has already been shown to provide some effect in solid tumors. Because these cognate interactions are hypothetical, their in vivo function remains to be determined.…”

Engineered Human Heavy-Chain Ferritin with Half-Life Extension and Tumor Targeting by PAS and RGDK Peptide Functionalization

“…It was designed by Schlapschy, and aimed to mimic poly ethylene glycol (PEG) [10]. In three previous studies, Falvo et al have fused 40 aa and 75 aa PAS peptides to human ferritin subunit at N-terminal to increase halflife in circulation [11][12][13]. Another peptide is a tetrapeptide named as RGDK.…”