Complement-Mediated Selective Tumor Cell Lysis Enabled by Bi-Functional RNA Aptamers.

Prabhat K Mallik,Kimi Nishikawa,Hua Shi,Pramit Mallik

doi:10.3390/genes13010086

Prabhat K Mallik, Kimi Nishikawa + Show 2 more

Open Access

https://doi.org/10.3390/genes13010086

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Abstract

Unlike microbes that infect the human body, cancer cells are descended from normal cells and are not easily recognizable as “foreign” by the immune system of the host. However, if the malignant cells can be specifically earmarked for attack by a synthetic “designator”, the powerful effector mechanisms of the immune response can be conscripted to treat cancer. To implement this strategy, we have been developing aptamer-derived molecular adaptors to invoke synthetic immune responses against cancer cells. Here we describe multi-valent aptamers that simultaneously bind target molecules on the surface of cancer cells and an activated complement protein, which would tag the target molecules and their associated cells as “foreign” and trigger multiple effector mechanisms. Increased deposition of the complement proteins on the surface of cancer cells via aptamer binding to membrane targets could induce the formation of the membrane attack complex or cytotoxic degranulation by phagocytes and natural killer cells, thereby causing irreversible destruction of the targeted cells. Specifically, we designed and constructed a bi-functional aptamer linking EGFR and C3b/iC3b, and used it in a cell-based assay to cause lysis of MDA-MB-231 and BT-20 breast cancer cells, with either human or mouse serum as the source of complement factors.

Highlights

In cancer therapy, the preferred targets are cancer cells rather than individual molecules, and the preferred outcome is irreversible destruction rather than reversible neutralization.Many approaches to cancer treatment, including the binding of inhibitors to active protein sites, can only reversibly neutralize targets at the molecular level
If the malignant cells can be earmarked by a synthetic “designator”, the powerful effector mechanisms of the immune response may be recruited to treat cancer
This approach is conceptually analogous to targeted drug delivery, but the “drugs” being delivered are patient- or hostderived factors and cells that are able to put on a powerful immune response with higher specificity and fewer side effects

Summary

Introduction

Many approaches to cancer treatment, including the binding of inhibitors to active protein sites, can only reversibly neutralize targets at the molecular level. At the cellular level, when appropriate markers are available, they may be utilized for targeting and destruction of specific cell types, which is a more powerful strategy for the eradication of cancer cells. If the malignant cells can be earmarked by a synthetic “designator”, the powerful effector mechanisms of the immune response may be recruited to treat cancer. This approach is conceptually analogous to targeted drug delivery, but the “drugs” being delivered are patient- or hostderived factors and cells that are able to put on a powerful immune response with higher specificity and fewer side effects

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