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Full seat of Village B | Qianbo Ming, CEO of Maibos Bio: Looking for the next PD-1 (L1) "Go Back to Science"

Full seat of Village B | Qianbo Ming, CEO of Maibos Bio: Looking for the next PD-1 (L1) "Go Back to Science"

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  • Time of issue:2019-11-28 15:06
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(Summary description)From doctors in neurobiology at Columbia University and Albany Medical College to postdoctoral and chief scientists at Amgen, ...

Full seat of Village B | Qianbo Ming, CEO of Maibos Bio: Looking for the next PD-1 (L1) "Go Back to Science"

(Summary description)From doctors in neurobiology at Columbia University and Albany Medical College to postdoctoral and chief scientists at Amgen, ...

  • Categories:Company News
  • Author:
  • Origin:
  • Time of issue:2019-11-28 15:06
  • Views:
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迈博斯From doctors in neurobiology at Columbia University and Albany Medical College to postdoctoral and chief scientists at Amgen, senior vice president and head of research and development at Sunoke Medical, and chairman and CEO of Maibos, For Qian Xueming, the change of identity is not only a journey to a new stage of life, but also a witness to the change of the antibody industry.

 

In the words of Qian Xueming, in the past 20 years, "antibodies" have been directly injected into the human body from the initial era of addition-protein drugs, immune factors, erythropoietin (EPO), etc., to subsequent subtraction The age—activating the body's autoimmune response through naked antibodies and neutralizing inhibitors, and entering the era of multiplication today—strong combination of multiple mechanisms of action such as combination therapy, bispecific antibodies, antibody conjugates (ADC) Play a therapeutic effect.

 

As one of the most popular antibodies in the "multiplication era", PD-1 / PD-L1 immune checkpoint inhibitors have attracted investment enthusiasm from large and small pharmaceutical companies worldwide in recent years. Today, in the field of oncology, almost every company wants to own PD-1 / PD-L1 products, and every company that owns PD-1 / PD-L1 tries to use it as a breakthrough to lead the combined tumor treatment.

 

However, PD-1 / PD-L1's standout has experienced some twists and turns, from a corner that is not favored and abandoned to a sought-after star of tomorrow, and its success does not rely solely on luck or clever clinical design. In Qian Xueming's opinion, whether it is exploring the next PD-1 / PD-L1-like target or becoming the pioneer of the commercialization of the next PD-1 / PD-L1 antibody, everything must return to science.

 

R & D differentiated science——How does PD-1 (L1) break through in the fierce competition?

 

As we all know, the tumor structure is very complex, the new blood vessels are intertwined to form a complex network, and the tumor microenvironment (TME) releases some factors to keep the drug out. If you only rely on passive diffusion of the drug, it is difficult to penetrate the tumor to reach the effective dose.

 

For the process of tumor immunotherapy using autoimmune cells to attack tumor cells, Qian Xueming vividly likened to the soldiers passing through the city walls to destroy the enemy soldiers guarded by layers. The soldiers battled with the enemy soldiers on the outside, and continued to transport the enemy soldiers on the inside. If there are fewer soldiers than the enemy soldiers, the soldiers may be wiped out when they fight the enemy soldiers. If there are far more soldiers than the enemy soldiers, some soldiers will always enter the city successfully.

 

"If an active mechanism is established to first destroy a wave of enemy soldiers or break the city walls, soldiers will be able to attack enemy soldiers closer to the city center faster and deeper." Based on this biological thinking, it is deeply influenced by Amgen's "science driven" philosophy Influenced Qian Xueming began to think about how to develop PD-1 / PD-L1 antibodies with differentiation characteristics. "If a complete tumor is simply divided into the outer layer, the middle layer and the inner layer, when all the drugs are delivered in the outer layer, the middle part starts to be delivered, so that at a certain point in time, the inner layer of the tumor maintains sufficient drug concentration, and the response rate of the patient will be Could be higher. "

 

迈 With the support of an antibody development platform based on immune tolerance barrier breakthrough technology (IMBT ™), Maibos has developed the world ’s first and only pH-dependent PD-L1 antibody. Currently, the product has started Phase I clinical trials in the United States. It is expected that in the second half of 2019, at least one registered clinical application will be launched for the application of the product to the market, and a number of clinical studies on combined use will be launched.

 

In fact, the application of pH-dependent technology to antibodies has a successful precedent. American orphan drug research and development company Alexion used pH-dependent technology to perform product lifecycle management on the basis of human-type anti-complement C5 monoclonal antibody Eculizumab for paroxysmal nocturnal hemoglobinuria. The second-generation product ALXN1210 developed by The drug cycle was extended from every two weeks to every eight weeks.

 

The currently published two comparative non-inferiority clinical studies have reached the clinical endpoint. Alexion will submit an ALXN1210 listing application in the United States, Europe, and Japan in the second quarter of this year. The next step is to continue to examine the possibility of subcutaneous injection.

 

In Qian Xueming's opinion, the most important application prospect of pH-dependent technology is to achieve better efficacy at lower doses and improve patient compliance by changing the frequency of administration, which is a great convenience for both patients and doctors. At the same time, the longer dosing cycle also allows the product to have some flexibility in future pricing, adding commercial advantages to the fierce PD-1 / PD-L1 market competition. "We want to allow antibodies to penetrate more deeply into the tumor, so as to achieve better tumor suppression and response capabilities, and extend the life of tumor patients as much as possible."

 

科学 The science of combined tumor therapy——How to find the optimal combination of "1 + 1> 2"?

 

According to the Evaluate Pharma report, as of April 2017, there were no less than 765 PD-1 / PD-L1 combination therapies registered on Clinicaltrials.gov, and some experts estimate that this number has soared to more than 1,000. The subjects of "PD-1 (L1) +" have gradually expanded from immunotherapy, targeted therapy, traditional radiotherapy and chemotherapy to cancer vaccines, oncolytic viruses, cell therapy, gene therapy and other treatment methods.

 

Although the combination therapy with PD-1 / PD-L1 as the backbone is an important trend in tumor immunotherapy and has become the consensus in the industry, there are still many doubting voices. "At present, a large number of combination therapies lack sufficient scientific basis," "This kind of Blind investment wasted too much R & D and clinical resources, "" The overcrowding of the PD-1 / PD-L1 circuit inhibited the development of other innovative targets. " The failure of a phase III clinical trial of the highly anticipated PD-1 antibody Keytruda and IDO inhibitor Epacadostat also undoubtedly poured cold water on the combination therapy in full swing.

 

In order to attack the city, large pharmaceutical companies will not hesitate to invest heavily in all possible combinations of potential success. Even small failures are enough to rely on the wide spread network to spread risks. However, for start-up R & D companies with limited resources, the consequences of failure may be unbearable The most important thing is how to formulate a combination therapy strategy to better balance the benefits and risks?

 

"The cost of tumor combination therapy is very high, so the choice of product combination must be based on a strong scientific mechanism." Qian Xueming believes that strengthening neoantigen presentation is an important theoretical basis for developing combination therapies. "Current benefits of monotherapy for tumor immunotherapy The population and extent are limited, and we hope to expand the response population through combination therapy, so that patients who have not responded, or patients who have responded very shallowly, will respond more deeply. "

 

There are enough neonatal antigens around T-cells around "hot tumors" represented by lung cancer and melanoma, and T-cells are inhibited by PD-L1 expressed on tumors. About 30% of patients pass PD-1 / PD-L1 There are benefits to monotherapy. At this time, the response population can be further expanded through combination therapy. For example, Bristol-Myers Squibb (BMS) "LAG3 + PD-1" combination therapy, proof-of-concept data show that this combination therapy helps patients with relapsed or refractory melanoma who receive PD-1 / PD-L1 therapy to overcome resistance To restore T cell function.

 

Qian Xueming said that for tumors with many immune cells around, the key to joint therapy is not only to give PD-1 / PD-L1 therapy to activate the combat effectiveness of soldiers, but also to let soldiers enter the city in a suitable way: one is to weaken the wall Stability, such as chemotherapy, the other is to clear the gates to allow soldiers to enter the city faster, such as anti-angiogenesis inhibitors. Roche PD-L1 antibody Tecentriq + anti-angiogenesis inhibitor Avastin + chemotherapy carboplatin and paclitaxel has been shown in a phase III clinical study to significantly prolong the survival of patients with advanced non-small cell lung cancer.

 

缺乏 The lack of immune cells near "cold tumors" represented by prostate and ovarian cancer makes it difficult for immune checkpoint inhibitors to play a role. It is imperative to treat these tumors to allow the immune cells to recognize the tumor cells. Based on this principle, Maibosi has proactively laid out MSB015, which targets the stimulation of antigen-presenting cells (Antigen Presenting Cells), and can increase the entry of T cells; targeting suppressive MF cells in tumors, it can release its inhibitory effects on T cells MSB013; and MSB003 for stroma cells.

 

According to reports, Maibos has formed a product line with PD-L1 antibodies as the backbone to supplement the functions of PD-L1 on various tumor subgroups. Of the 10 oncology research projects, 8 are related to immunotherapy and 2 are targeted therapies, of which multiple products can be used alone or in combination. The rich product line also provides the company's future combination therapy development plan. Gives strong support and more possibilities.

 

Although the prospect of combination therapy is widely optimistic in the industry, in addition to the cost burden of the combination of two or more products, the combination or synergy of the drug combination in toxicity will also make the benefit and risk full of uncertainty. . In addition, there is also the view that if the combination therapy cannot succeed in broad-spectrum indications, the commercial application prospects may be very limited.

 

In this regard, Qian Xueming believes that on the one hand, companies must find their own unique combination, form features in the preclinical and clinical trial design, and consciously explore the unsolved problems of scientific mechanisms. On the other hand, we should be good at taking advantage of opportunities for external cooperation, such as launching a combination with a marketed product or a more promising unlisted product, to maximize the development of combination therapies to the greatest extent and benefit more cancer patients early.

 

"The combination therapy ultimately competes for the choice of indications, and the thresholds for different tumor types are different. For example, some tumor indications already have many therapeutic products. Even if their own products have been proven scientifically successful, it is difficult to achieve commercial success. But If you find an indication that fits the mechanism of combination therapy and lacks effective treatment products, then it will be easier to achieve success in both the scientific and commercial sense. "Qian Xueming said.

 

科学 The Science of Entrepreneurship: Where is the core competitiveness of startups?

 

At the end of the 20th century, the launch of the Human Genome Project sparked a fever of gene sequencing. Many companies tried to find new targets for medicine by revealing the functions of unknown genes. I remember when I first joined Amgen, Qian Xueming was fortunate to have participated in a large-scale genome sequencing project of the company at that time. The project convened 150 people for three years and spent $ 400 million to find genes that could be developed into protein drugs. What impressed him was that Amgen did not achieve the expected goal at the end of the plan, but unexpectedly harvested many targets that could be developed into antibodies.

 

Since then, Amgen has shifted some of its research and development efforts to the antibody field, and billion-dollar blockbuster products have been born. Qian Xueming has also grown from a project participant to a project leader, leading a small team of more than a dozen people including antibody discovery, pharmacodynamics, toxicology and pharmacology, process development, early clinical, patent application, commercial development, and marketing. Apply for resources, develop and implement development plans. This "internal entrepreneurship" experience also gave him a deeper understanding and comprehensive understanding of the antibody development process.

 

After entering the 21st century, the antibody industry has ushered in rapid development: more and more targets have been developed into antibody drugs, and antibody analysis has been upgraded from simple basic structural analysis to three-dimensional and four-dimensional spatial analysis; the expression of cell lines producing antibodies has changed from the earliest 1-2g / L increased to the current 5-7g / L; the field of antibody therapy has expanded from tumors, autoimmune diseases to brain diseases, infectious diseases; antibody patent protection has also extended from traditional sequences to a wider range of Dosage forms, production techniques and even epitopes.

 

随着 Now that the results of the Human Genome Project are showing results, scientists have become more and more aware of genes, and the threshold for developing antibodies has been significantly reduced compared to two decades ago. This is the best era of entrepreneurship. Under the innovative atmosphere created by many favorable policies, a small and beautiful team, capital support, and mature CDMO services, it is possible to realize an antibody drug from scratch. "This is an opportunity and a challenge. It is very difficult for latecomers to make a difference on the targets that everyone knows. This also drives them to invest in new fields from another aspect." Qian Xueming admitted.

 

"Just a swarm of bees chasing hotspots will not lead to new breakthroughs. Why can TNF-α targets develop so many indications? Why do EGFR-targeted drugs achieve significant results in non-small cell lung cancer with EGFR mutations? Biology plays an important role in it. "In Qian Xueming's view, the reason why PD-1 / PD-L1 achieved the dazzling results today is that Science theory is behind it.

 

To replicate the success of "PD-1 / PD-L1", Qian Xueming believes that on the one hand, China should increase investment in basic research, find new biological mechanisms and tap its potential application value, especially for general-purpose organisms. Learning mechanism. For example, fibrotic diseases are a large class of diseases that include pulmonary fibrosis and liver fibrosis. If a common mechanism of action is found for these diseases, then potential stocks suitable for multiple indications can be developed. At present, Maibosi has deployed a First-in-class product that targets fibroblasts. Preclinical studies have shown that this product has good therapeutic potential and will continue to be verified in human clinical trials in the future.

 

On the other hand, the investment community and the business community must also strengthen close cooperation with scientific research institutes in colleges and universities to transform original ideas into products with clinical application value. "At present, the human genome is only revealed by 10%, and more unknown gene functions rely on companies to develop a series of innovative technologies to clarify."

 

谈 When talking about how to establish the core competitiveness of enterprises in the current tide of biomedical entrepreneurship, Qian Xueming once again emphasized the importance of Biology and Science theory. "We must invest a lot of research in biological mechanisms, whether in the technical field, the therapeutic field, or other fields, to do things that others don't or can't."

 

"Molecules determine the value of the company, and the core lies in how people and founders gather a professional team to maximize the potential of the product in the established strategic direction through their own technology platform or other people's technology platforms. Changes can be adjusted to the company's strategy in a timely and flexible manner. "Qian Xueming further pointed out," Of course, companies will continue to strengthen their core competitiveness in the development process, such as sales teams, business strategies, etc. "

 

"The development of an enterprise is like a fish swimming in the sea. If you have a good product, where you swim will not become an obstacle that restricts the development of the enterprise. The external environment is important, but how far you can truly swim depends on your own internal Strength. "Qian Xueming emphasized.

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