See how the "K medicine" in the immune age turns against the wind

In October 2020, the annual Nobel Prize in Physiology or Medicine was awarded to Harvey J. Alter, Michael Houghton and Charles M. Rice in recognition of the three men's contribution to the discovery of the hepatitis C virus.
the Nobel Prize in Physiology or Medicine in recent years, we will find that many of the winners' reasons for winning are closely related to the discovery or treatment of major diseases, and we are talking about cancer immunotherapy, which is actually related to the Nobel Prize.
Bring Time Back to October 2018, when the Nobel Prize in Physiology or Medicine was awarded to James Allison of the United States and Ben Yu of Japan for their outstanding contribution to the promotion of oncology immunotherapy, which has once again become the focus of global attention.
James Allison (left) and Ben Yuyou (right) (pictured on the Nobel Prize website: when it comes to immunotherapy, it's certainly not the word "K medicine."
so-called
K drug" is actually a PD-1 antibody drug from MSD, short for Pembrolizumab, a human-source monoclonal antibody named After Keytruda.
The drug is a human-sourced monoclonal antibody, used to treat melanoma and other solid tumors, at the same time the "O drug" developed by BMS is the main competition, and "O drug" based on Ben Yu and Chinese-American scientists display Ping patent development, the initial market has become a scenery of the drug, until the "K drug" later rose , "O.K. " situation began to change.
I, life is not the right time, a wave of three folds, "hard-living children" difficult birth now sounds, K medicine as the representative of a series of increasingly mature immunological drugs and the action of the machinery is so logical, but just over a decade ago, in addition to a few fanciful "pioneers", I believe that immunotherapy cancer has the benefits of industry experts can not find a lantern.
K medicine, destined to go through some ups and downs.
2003, Oganon in the Netherlands began looking for an agitant for pD-1 receptors, hoping to passivate immune T cells by infesting PD-1 receptors, thereby achieving the goal of treating autoimmune diseases.
the project was intended not only to have nothing to do with cancer treatment, but also to the contrary to the prevailing thinking in the industry at the time.
in 2005, the team didn't get any good agitants, but unexpectedly got high-activity antagonists.
while the team did not know how to use the antagonist, Oganon scientists Gregory Carven, Hans van Eenennaam, John Dulos and others at the time considered it over and over again and decided to try the controversial cancer immunotherapy.
the antibodies in the hands of the team came from mice, were not compatible with the human body and could not be used in clinical trials except for preclinical studies.
then, in 2006, they found the British Medical Research Council (MRC) and worked with MRCT, its research arm, in the hope of obtaining a humanized version of the antibody.
MRCT successfully delivered highly active, highly humanized monoclonal antibodies to the Oganon team in 2008, Pembrolizumab took a critical step forward.
: MRCT introduced the antibody humanization technology to Oganon at BIO in 2006, Oganon and MRCT in 2007, MRCT delivered humanized monoclonal antibodies to Oganon in 2008, and Pabli Pearl Monoantitor was approved for listing by the FDA in 2014.
However, before Oganon began any substantial research on this human-sourced monoclonal antibody, Oganon was acquired by Shilling-Ya for $14 billion, and the antibody project, which had just begun, entered the name of Shilling-Ya.
Unfortunately, when Shilling-Ya's senior management evaluated Oganon's research project, because no one was optimistic about the PD-1 antibody project at that time, this Oganon was considered a high-priority project, which was reduced by Shilling-Ya.
, although not favored by the top, the company organized a project team to design clinical studies of antibodies in accordance with the normal drug development process and began to discuss how to proceed.
may have been in God's own way, and just when Shilling-Ya was unsaceing if he wanted to put the project into clinical practice, it was merged by the American pharmaceutical giant Mercer East.
2009, another post-merger integration and project evaluation.
this time, the PD-1 antibody was not so lucky: the project's development team was disbanded by Mercedon, and the antibody was labeled for sale, so long as it was willing to pay a price, it could be packed and taken away.
at this time, Mercedon has not yet focused on the field of cancer drugs.
, it wasn't particularly surprising when Mercedon decided to terminate the project and disband the development team.
other cancer drug giants at the time, and they didn't see the potential value of the antibody, watching it sit quietly on the shelves and miss out.
is this valuable antibody molecule really dead like this? Between and again! A paper by rival Shishi Shiguibao turned the situation around.
2, seize the opportunity, bend over the car, take the "immune wind" to break the "tumor wave" helplessly partial to this section of the bone eye, the big meaning of the hundred-time Meishi Guibao initiative "to send the head", luck finally came on the body of K medicine.
time is not too late, as recently as 2010, when the New England Journal of Medicine first published the successful Phase III clinical study of the treatment of refractic metastatic melanoma by Ipsos (commodity name Yervoy), the drug targeted the drug although different from PD-1 but related to the T-cell inhibitor molecule CTLA4, but foreshadowed the feasibility of the test point inhibitor, which made the mainstream view of the field of cancer immunotherapy changed.
news that The New York Post followed, the acquisition of the early PD-1 molecule Nivolumab, or O-drug, by acquiring Medarex also showed some promising signs.
of cancer immunotherapy, once again into the public eye.
's olfactory top management seemed to sniff out the huge prospect of cancer immunotherapy, adjusting its research and development strategy to get back the fast-eating antibodies on the shelves while thanking the PD-1 antibody, which quickly reorganized the project team, submitted a new drug application (IND) to the FDA at the end of 2010 and began recruiting clinical trials for the first clinical trial in early 2011.
an efficient research and development team was quickly assembled.
but Mercedon has nothing to celebrate, and waiting for them is a very serious challenge, and it's just getting started.
Based on the information at the time, it appeared that Segber's PD-1 antibody had submitted a new drug application to the FDA as early as 2006, and that Mercado, who had just entered the racetrack, was four years behind its rivals and wanted to catch up with Shguibao, which seemed like an "impossible mission."
the project team at Mercedon didn't mess with themselves, and they quickly de-designed an aggressive clinical development plan to try to achieve corner oversized cars.
, an antibody development that you chased me opened up.
2011, drug K entered Phase I clinical trials as scheduled.
Phase I clinical and other clinical studies, the study of dosage, the study of safety and tolerance for advanced patients, as well as some effectiveness experiments, is a typical Phase I process.
phase I results showed that the results were particularly satisfactory for patients with the corresponding melanoma of PD-1, so the team locked the scope of the experiment on melanoma.
results were shocking, with six of the first seven subjects showing objective responses.
early results showed very positive clinical data, which greatly enhanced the confidence of the entire team.
's research and development team decided to expand the scope of Phase I clinical trials to a clinical trial group of 655 metastasis melanoma patients and a similar number of lung cancer patients, making it the largest Phase I clinical trial in the history of oncology drug development.
only the large-scale success of clinical trials, not enough to allow Mercedon to achieve corner oversized.
2012, the FDA plans to implement a "breakthrough therapy identification" (BTD) policy that allows new drug approvals to be approved more quickly.
fortunately, at an international safety research conference, a non-clinical safety chief in Mercedon came to this very important message from a former FDA colleague.
In view of the positive results of the Phase I clinical trial of melanoma, Mercadon was the first to apply for and qualify for BTD for the K drug in January 2013, becoming the second experimental drug to do so since the policy was introduced.
but Mr Mercedon did not release the news because it did not want potential competitors to speed up the listing through the policy.
: PD-1 is a trans-membrane programmed cell death 1 protein (also known as PDCD1 and CD279).
as an immune checkpoint molecule, it interacts with PD-L1 (PD-1 liup 1 or CD274).
PD-L1 on the surface of the cells binds to the PD1 on the surface of the immune cells, thereby inhibiting the activity of the immune cells.
in order to induce negative regulation of T cells at PD-1 checkpoints, many tumors express PD-L1.
Paboliju single anti-inhibition T cells and tumor cells between PD-1 and PD-L1 checkpoint binding, thus inducing the immune response response in melanoma clinical trials progressing smoothly, the team also focused on the field of non-small cell lung cancer (NSCLC), ready to use the drug for NSCLC second-line treatment.
It is worth mentioning that, although in the rush of Mercado, the project came to the press, but after all, the project restart is several years later than hundreds of times Meishi Guibao, want to really get rapid approval to go public, or in the second-line treatment to show an ultra-high response rate.
's development team finally got a look at the biomarker, which was controversial at the time, and boldly chose PD-L1 molecules that could be highly expressed on tumor surfaces as markers to help researchers more effectively screen patients who could receive an immune response.
Although the use of biomarkers to screen patients has been controversial and questioned, clinical trial results have shown that good results have been achieved in non-small cell lung cancer and tumor symptoms such as triple-negative breast and stomach cancer.
methods proved to be feasible, and the bold decisions of the Mercedon team were in the right direction.
took up all the time and land, K medicine finally succeeded in achieving the corner oversized.
September 4, 2014, the FDA officially approved the listing of the drug K, making it the first PD-1 antibody drug to be approved for advanced melanoma treatment in the United States.
In the U.S. mainland, from the declaration to the market, K drug only took 164 days, and at this time the hundred-time Meishi Guibao is busy preparing to file a lawsuit against Mercado, which makes K drug than the same drug O drug was approved more than 3 months earlier, fate, late start of K medicine finally ushered in their own "open life."
Three, large device late into, covered with thorns, eventually become a generation of "Immune King" holding the world's first PD-1 antibody, Hundred Times Shiguibao layout of a high PD-1 patent barrier, in the key patent (EP1537878) is the PD-1 functional limit rights protection, that is, PD-1 antibody for tumor treatment has made a lot of restrictions.
's not easy to get around these patent barriers.
the same night that K-Drug was approved by the FDA, The Hundred-American Sequoig and Ono Pharmaceuticals filed a formal lawsuit against Mercado, an inevitable patent battle that was on the way.
good news, after more than two years of fighting between Mercado and Shi Guibao/Ono Pharmaceuticals, on January 20, 2017, the two sides finally signed an agreement on the patent litigation of PD-1 mono-resistance: Mercado wants A down payment of $625 million was made to Shiguibao/Ono Pharmaceuticals, as well as 6.5 percent of K-drug sales in 2017-2023 and 2.4 percent of K-drug sales in 2024-2026.
although Mercedon had to pay his "late" tuition fees, K medicine finally cleared the last hurdle on the road to the king.
, who took over as head of research and development in 2013, announced on October 3rd that Dr Roger Perlmutter would retire at the end of his seven-year term. Mercadon's breakthrough in tumor immunotherapy has also greatly enriched Mercadon's research and development pipeline, fully aware of the huge potential of K medicine, he will be antibody development potential back to the decision-making level, Mercadon decided that no cost, ordered departments to do their best to do all the clinical research of K drug.
clinical trials, which should have been conducted in chronological order, have now been changed to parallel trials at the same time.
with a series of Phase III clinical trials, the K drug has accelerated its march.
since the launch of K and O drugs in 2014, in order to occupy a larger market share, O and K drugs in the adaptation, patent competition, when Opdivo in the number of adaptations, Keytruda focused on the lung cancer market and won.
bold design of clinical trials to enable the successful counter-attack of the K drug.
Q2 2018, Drug K began to catch up with O drugs and surpassed O drugs by $6,735 million in 2018 with annual revenue of $7,171 million, while O drugs began to change their heads in the PD-1 chair due to a succession of breaks in critical Phase III clinical trials.
with its strength in adaptive disorders and sales, drug K surpasses competing O-drugs, and "O.K. completes "K.O"! Figure: Timeline chart for Keytruda's FDA approval of allergy by 2019: 201