Before the Pfizer-BioNTech COVID-19 vaccine authorization, there were no mRNA therapies approved anywhere in the world. The idea of using messenger RNA as a way to get your body to be the drug manufacturer has been around for some time, but only in recent years has it become practical. And it was the COVID-19 pandemic that provided the opportunity for the technology to push ahead with COVID-19 vaccines from Pfizer-BioNTech and Moderna.

Complementary to one of the DNA strands of a gene, mRNA is a single-stranded RNA molecule. The mRNA’s job is to deliver that code to ribosomes, which is the part of the cell that produces proteins. In the case of mRNA therapeutics, a synthetic mRNA is designed that codes for a specific protein. It is encapsulated in a minuscule bit of fat called a nanolipid particle. When injected, the cellular machinery takes up the mRNA and produces the protein it codes for. In the case of the COVID-19 vaccines, the mRNA codes for a piece of the SARS-CoV-2 virus’s spike protein, which the virus uses to enter human cells.

In short, mRNA therapies and vaccines are a way of turning the body into its own drug manufacturer. Even before the COVID-19 pandemic, Moderna was focused largely on infectious diseases and vaccines, with programs for influenza A, Chikungunya virus, Zika virus, Cytomegalovirus, human metapneumovirus (HMPV), parainfluenza virus (PIV3), and others. Many in the field felt that vaccines were “low-hanging fruit,” easier to work towards, even if vaccines are not a hugely lucrative business overall. But both Moderna and BioNTech had their eyes set on trickier uses for mRNA therapies—cancer, for example.

Derek Thompson, with The Atlantic, recently interviewed the husband-and-wife team that co-founded Germany’s BioNTech, Dr. Ugur Sahin and Dr. Ozlem Tureci. On October 1, the company announced that it had treated the first colorectal cancer patients in a Phase II trial. It is testing its individualized mRNA cancer vaccine BNT122 (autogene cevumeran). The study is being run in the U.S., Germany, Spain, and Belgium and expects to enroll about 200 patients.

The trial will evaluate the effectiveness and safety of the vaccine in colorectal patients after they had surgery for their tumor and completed adjuvant chemotherapy. The current standard of care in that situation is “watchful waiting.” The study will evaluate the drug in that context compared to the watchful-waiting cohort.

Autogene cevumeran is an individualized neoantigen specific immunotherapy (iNeST). It contains unmodified, pharmacologically optimized mRNA encoding up to 20 patient-specific neoantigens, which are cancer proteins different from those produced by healthy cells but are recognized by the immune system. The mRNA is enclosed in the company’s proprietary intravenous RNA lipoplex delivery formulation.

Moderna, for its part, on its 2021 R&D Day on September 9, provided an overview of its mRNA portfolio. It included a number of vaccines for infectious diseases, but also a Phase II trial of a personalized cancer vaccine (mRNA-4157) in combination with Merck’s checkpoint inhibitor Keytruda (pembrolizumab) for adjuvant treatment of high-risk resected melanoma; a Phase IIa study of AZD8601 VEGF-A for ischemic heart disease patients undergoing coronary artery bypass grafting surgery, which AstraZeneca is leading; and its rare-disease program, which includes enrollment in the first cohort in the Phase I/II Paramount study in Propionic Acidemia (mRNA-3927).

At the event, Stephane Bancel, Moderna’s chief executive officer, stated, “I am proud of the progress that the Moderna team has made in advancing our best-in-class mRNA pipeline while addressing the global COVID-19 pandemic. We believe our mRNA platform can solve the world’s greatest health challenges, from diseases impacting millions to ultra-rare diseases impacting dozens, to medicines personalized down to the individual level.”

When it came to the COVID-19 vaccines, Moderna reportedly designed their vaccine within 48 hours of receiving the viral genome and Sahin said, “Actually, we (BioNTech) did it in less than 48 hours! In 24 hours, we generated the genetic sequence of the first eight vaccine candidates.”

Thompson asked Sahin and Tureci why mRNA worked out so well against COVID-19. Sahin noted, “I think it may be the mother of all questions. Before corona, there was Ebola, and a different vaccine technology that was viral-vector-based was sufficient. Ebola was low-hanging fruit for viral-vector-vaccine technology. The coronavirus is a very different virus. It has these spike proteins that bind very strongly to the receptors [of our cells]. It turned out that mRNA vaccines were particularly excellent for boosting the immune system’s response. So maybe the coronavirus was lower-hanging fruit for mRNA technology.”

In terms of cancer, Tureci says BioNTech has two types of mRNA vaccines for cancer. “First, we have our off-the-shelf vaccines, where we’ve identified molecular features of tumors that are shared by many patients. These are molecules that are broadly present in cancer cells but not in normal cells. By targeting these molecules, you can fight the cancer without getting collateral damage to healthy cells.”

She went on to say, “Second, we have highly personalized vaccines. We identify cancer mutations that are unique to every patient. Every cancer patient has their own mutations, like a fingerprint. We biopsy the tumor, sequence it, and design a unique, individualized vaccine for each patient.”

Sahin and Tureci are optimistic about the future of mRNA vaccines for cancer, but Sahin notes they’ve just moved to Phase II trials where they will have to prove “that our therapy beats the standard of care the patient would otherwise get. It would only be scientifically sound to gauge the vaccines after this head-to-head comparison. We think we can make major advances in the next five years, but it really depends on what these Phase II studies show us.”

Meanwhile, mRNA technology has been successfully dosed in more than a billion people around the world and is the pathway to ending the COVID-19 pandemic.

출처: Biospace

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