Self Renew column｜Targeted anti-tumor therapy derived from autoimmune diseases—review a 2016 article

In the field of anti-tumor drug research and development, the industry has never stopped trying to achieve precise drug delivery to increase the treatment window.

To improve the tendency of drugs to be enriched in tumor sites, antibodies are an ideal guidance tool.
Not only can they be used as drugs by themselves, they can also be used as a component of complex drugs (such as ADC) to help active drug molecules reach the lesion more accurately .

And if the targeting of antibodies is ensured, the choice of antigen is crucial.

At present, it can be said that most people are looking for antigens on membrane proteins, repeatedly demonstrating the expression abundance, specificity, and whether the expression level of membrane proteins is affected by the microenvironment and so on.

Of course, for ADCs, targeting membrane proteins is one of the necessary conditions for endocytosis, but from the perspective of broader targeted drug delivery development, our vision can be broader.

This is my little understanding after looking back at an article in 2016.

One of the important differences between the microenvironment of tumors and healthy tissues is that the tumor site contains a large amount of extracellular DNA, which is caused by the rapid proliferation of cancer cells, a large number of apoptosis or necrosis, and the NET of neutrophils.

If antibodies that target extracellular DNA can be used, we have the hope of achieving precise delivery of anti-tumor drug molecules.

The most obvious advantage of using antibodies targeting extracellular DNA to guide the delivery of chemotherapeutic drugs lies in a positive cyclic effect caused by the mechanism of action: drug molecules accumulate at the tumor site rich in DNA molecules, effectively killing cancer cells and killed cancer cells Release the DNA in the lower cells, thereby further increasing the concentration of DNA in the microenvironment, attracting more drugs to approach.

In this way, as the treatment progresses, the antigen at the tumor site not only does not decrease, but increases, so as to maintain or even continuously improve the delivery effect of the drug.

This is why this method is described as "autocatalytic".

The pathogenesis of systemic lupus erythematosus, an autoimmune disease, is believed to be related to autoantibodies that target genomic DNA produced in the body.
3E10 is a DNA-targeting antibody isolated from a mouse model of SLE.

It can penetrate the nucleus and inhibit the repair of genomic DNA, and this ability depends on the presence of extracellular DNA.

Researchers in the laboratory made mutations to 3E10 to increase its affinity for DNA, and then modified the nanoliposomes packed with doxorubicin (DOX) with a mutant (3E10EN), which was used in a mouse breast cancer model.
Test the effectiveness of this targeted drug delivery system.

The imaging results show that the 3E10EN modified DOX liposomes can be specifically enriched in the tumor site in mice, but not in the liver, heart, muscle and other important organs and tissues.

From the actual effect point of view, 3E10EN modified DOX liposomes can indeed significantly inhibit the growth of breast cancer xenografts.

In addition, 3E10 itself inhibits the repair of genomic DNA and has a "synthetic lethal" effect similar to PARP inhibitors.

Therefore, the killing of cancer cells by this delivery system may be multifaceted.

At present, this idea has also been applied for a patent, and it is expected that it can show its value in the future research and development of new drugs.

The editor commented that there are many large and small discoveries in basic research.
As workers in the pharmaceutical industry, we need to have a pair of eyes to discover beauty, or we need to be sensitive to the transformational value of scientific research results.

In this way, we can hope to get out of the situation of involution and present a prosperous scene of contention among a hundred schools of thought.

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