Targeting Antitumoral Proteins to Breast Cancer by Local Administration of Functional Inclusion Bodies

Abstract

Two structurally and functionally unrelated proteins, namely Omomyc and p31, are engineered as CD44‐targeted inclusion bodies produced in recombinant bacteria. In this unusual particulate form, both types of protein materials selectively penetrate and kill CD44+ tumor cells in culture, and upon local administration, promote destruction of tumoral tissue in orthotropic mouse models of human breast cancer. These findings support the concept of bacterial inclusion bodies as versatile protein materials suitable for application in chronic diseases that, like cancer, can benefit from a local slow release of therapeutic proteins.

Blocking Myc to Treat Cancer: Reflecting on Two Decades of Omomyc

“…As expected, both Omomyc IBs and GFP control IBs were internalized into CD44+ TNBC cells in vitro through an endosomal route, but only Omomyc IBs had a cytotoxic effect on tumor cells [87]. In addition, the authors showed that, while weekly intratumoral injections of Omomyc IBs in a TNBC orthotopic cell-line derived mouse model caused no changes in tumor volume, they did increase p21 protein levels, suggesting some block of proliferation, and induced tumor necrosis [87]. As for FPPa-Omomyc, PK and systemic toxicity of Omomyc IBs should be evaluated before further development (Table 1).…”

“…When cells are lysed and soluble recombinant proteins collected, IBs are usually discarded [92]. However, given the notion that they can attach and penetrate mammalian cells and act as slow release protein platforms, Pesarrodona et al produced Omomyc-FNI/II/IV-H6 IBs in E. coli and tested their anti-tumor efficacy in TNBC models in vitro and in vivo [87]. FNI/II/IV binds CD44, a transmembrane glycoprotein implicated in cancer development and progression [93].…”

The Biological Potential Hidden in Inclusion Bodies

“…Many examples have been published during the last decade that prove that IBs are protein-based biomaterials with promising characteristics to be used for cell replacement therapies, for tissue engineering purposes, or even for cancer treatment [3][4][5][6][7][8][9][10][11]24], among other applications. However, their characteristics and their in vitro behavior have never been correlated with their in vivo performance compared with other standard formats.…”

“…In vivo, Unzueta and co-authors observed that subcutaneously injected tumor-targeted IBs could release the forming protein, cross into the blood stream and accumulate in the tumor for sustained periods [9]. In addition, when intratumorally injected, IBs made of therapeutic proteins, such as Omomyc and p31, induced tumor cells' death [10], while cytokine-based IBs administered intraperitoneally conferred protection to zebrafish model from a lethal bacterial infection [11].…”

Influence of the Dextran 70 on Aggregation Antitumor Cytokine Emap Ii

“…Слід зазначити, що фармацевтичні препарати на основі білків проявляють більшу специфічність щодо мішеней та меншу токсичність. Білкові терапевтичні засоби використовуються в широкому спектрі медичних застосувань, включаючи гормональну терапію, онкологію, аутоімунні порушення, а також як протиінфекційні агенти [1,2]. Одним із складних аспектів фармацевтичної розробки терапевтичних засобів на основі білків є значна лабільність їхньої структури, що робить цей клас препаратів дуже сприйнятливим до деградації під час виробництва, зберігання та введення в організм в якості лікарських препаратів [3].…”