3E10 is a lupus auto antibody that penetrates live cell nuclei by binding to DNA or its precursors outside of cells and then following it into cell nuclei through a nucleoside transporter. Once in the nucleus 3E10 interferes with DNA repair processes, but the degree of inhibition of DNA repair caused by 3E10 is modest and is not enough to kill a normal cell that has robust mechanisms to manage insults to DNA. On the other hand, many cancer cells are exquisitely sensitive to DNA damage because their DNA repair machinery is already impaired. When these cancer cells encounter 3E10, they accumulate more DNA damage than they can handle and ultimately die. 3E10 is therefore selectively toxic to cancer cells that have deficiencies in DNA repair, which includes a wide range of malignancies such as gliomas, melanomas, prostate, breast, and ovarian cancers and many others. When combined with DNA-damaging agents such as chemotherapy or radiation, 3E10 has an even greater effect on these cancer cells.
3E10 is particularly well suited for use in cancer therapy because it preferentially localizes to tumors but not normal tissues. As tumors grow and go through cycles of proliferation they are constantly releasing DNA, and this results in accumulation of a “cloud” of DNA in the tumor vicinity. 3E10 is specifically attracted to DNA, and moreover is dependent on the presence of extracellular DNA in order to penetrate cell nuclei. The cloud of DNA in the tumor vicinity therefore not only attracts 3E10 to the area, but then also facilitates nuclear penetration by 3E10 into the tumor cell nuclei where it then inhibits DNA repair and kills the tumor cells and sensitizes them to DNA-damaging agents.
To prepare 3E10 for clinical trial testing, it will be modified to remove any components that could carry a risk of causing lupus-like side effects. In addition, 3E10 will be optimised to enhance its binding to DNA and increase its effect on DNA repair-deficient cancer cells. 3E10 is currently in preclinical development.
5C6 is another lupus autoantibody that penetrates live cell nuclei, similar to 3E10 is highly toxic to cancer cells with DNA repair deficiencies and has similar potential to be used in cancer therapy.
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