The global position of China's antibody drugs: not only in quantity, but also in innovation!

All over the world, biological drugs, especially antibody drugs, have begun to break out their vitality after years of basic research and technology accumulation, and become the most dynamic and promising branch in the field of drugs Even excluding the monoclonal antibody biosimilar, there are at least 85 antibody drugs that have been approved for marketing in the world, and the sales volume is expected to exceed 100 billion US dollars this year The whole field is thriving In China, with the support of policy, the favor of capital and the return of a large number of technical talents, the research and development and industrialization of antibody drugs have also risen rapidly in recent years, with the continuous improvement of technology level and the continuous expansion of industrial scale With the improvement of R & D level and the international vision of returnees, the whole industry will gradually upgrade its thinking level from domestic to global from R & D to sales It is one of the important manifestations of this trend to apply for the clinical research application (ind) of new drugs to the U.S Food and Drug Administration (FDA) The author makes a summary of the antibody new drug R & D projects and their R & D enterprises that have successfully applied for ind in the United States so far, and makes a brief analysis, hoping to see through the development status and trend of China's biomedical industry [overall situation] pragmatic and differentiated domestic R & D layout table 1 basic information of antibody drugs successfully applied by domestic pharmaceutical companies for ind in the United States (Note: progress of clinical trials in the United States as of November 11, 2017) up to now, the author has collected 11 Some domestic pharmaceutical companies have applied for the successful antibody drugs of ind in the United States (see Table 1) From the perspective of enterprises, the declared enterprises are not only traditional enterprises such as Hengrui medicine and Kanghong medicine, but also start-ups such as Corning Jerry and Baiji Shenzhou, indicating that the scientific nature and market potential of biological drugs (especially antibody drugs) have been generally recognized by the domestic medical and pharmaceutical industry From the perspective of the target selection of the declared drugs, they are all relatively popular targets with no obvious innovation However, careful analysis shows that most of these drugs are different from most of the same target drugs that have been on the market or are under research For example, the structure of kn035 of kangningjierui / thingdi is a single domain antibody, which is the only one in the known drugs on the market and in the clinical research of the same target antibody After verification, kn035 can be preserved at room temperature, and the administration method in clinical trials is subcutaneous injection, with obvious advantages Compared with Aflibercept, conbercept of Kanghong Pharmaceutical Co., Ltd adjusted the structure of the receptor part of the fusion protein The hlx06 of Fuhong Hanlin is a monoclonal antibody against VEGFR2 Compared with the same target monoclonal antibody, the antigen binding epitope of ramucizumab hlx06 of Lilly is different It is expected to achieve the difference of therapeutic effect by changing the mechanism of action of the antibody while avoiding the patent Bgb-a317 of Baiji Shenzhou has been engineered in FC segment, eliminating the binding ability of FC segment and its receptor, weakening the antibody dependent cell phagocytosis (ADCP) effect caused by FC segment, which is expected to further reduce the potential side effects of antibody; at the same time, the high temperature resistance and acid resistance of antibody have also been improved It can be seen that some of these differentiation strategies are reflected in the selection of target protein binding sites, some are reflected in the selection and transformation of drug structure, and the ultimate goal is to make the drug obtain certain clinical advantages, so as to ensure that it can occupy a place in the fierce competition, which is what we understand as "me better" This is a more pragmatic strategy for the emerging domestic biomedical industry From the perspective of clinical application, Australia is selected for the first clinical application of some drugs, such as bgb-a317 of Baiji Shenzhou and f-627 of jiannenglong This is because the clinical application time in Australia is short and the cost is low, and the clinical data can be recognized by the United States and the European Union This is a good choice for the start-ups with fierce competition in R & D, or with relatively tight R & D funds Most other drugs gradually choose to declare to FDA and domestic CFDA at the same time, especially in the context of China's accession to ICH, it is believed that this China US dual reporting method will become the main way for domestic enterprises to declare in the future [highlight varieties] detailed analysis of innovation projects worthy of expectation Hengrui shr-a1403 (anti-c-Met antibody drug conjugate): ADC products have technical advantages over other c-met ADC projects in the world Among 11 successful antibody drugs reported by domestic pharmaceutical companies to ind in the United States, shr-a1403 of Hengrui is the only antibody drug conjugate (ADC) Its target is tyrosine kinase receptor c-Met, which is a growth factor receptor highly expressed on the surface of various types of cancer cells, and is involved in the occurrence and deterioration of cancer From the current drug development situation of c-met target, the failure rate is high In terms of small molecules, there are many research projects, and the drugs on the market, such as crizotinib, are various tyrosine kinase inhibitors, not targeted drugs; in terms of antibodies, there are no drugs approved, which are generally in the early clinical stage, and the fastest-growing roarter's onartuzumab is also in phase III halberd The possible reasons are as follows: 1) the activation mechanism of c-met is more complex, simply blocking its binding with ligands does not necessarily inhibit its activation; 2) the downstream signal pathway has cross or compensatory effect with the downstream signal pathway of other targets (such as EGFR), which will weaken the inhibition effect of drugs on it Therefore, on the whole, single drug therapy of c-met target drug is not an effective method At present, the commonly used improvement methods include the combination of other anticancer drugs, the development of bispecific antibodies, and the development of ADC drugs The characteristic of ADC drugs is that this treatment strategy does not require the antibody to function, but only requires it to be able to specifically bind to antigens and cause endocytosis, and to accurately carry small molecule drugs to the tumor cells and release them Therefore, in theory, as long as cancer cells express c-met highly, ADC drugs can kill them accurately It's a very clever design At present, there are three ADC drugs in research for the target of c-Met, i.e abbv-399 of Albright, sti-0602 of Sorrento and shr-a1403 of Hengrui The fastest progress is abbv-399, which is currently in phase I clinical The antibody part of shr-a1403 was made by immunizing mice with antigens to prepare hybridoma, screening positive clones, and then transforming them into human beings; the toxin part was made of new toxin independently developed by Hengrui Among the three drugs under study, only shr-a1403 uses site-specific coupling technology, which helps to control the drug's Dar (drug anti ratio) value and purity Previous functional experiments showed that shr-a1403 could effectively kill cancer cell lines with specific expression of c-met protein, and the effect was significantly stronger than that of single antibody, while it had no significant killing effect on cell lines with no or low expression of c-met; animal experiments also proved that shr-a1403 could effectively inhibit the growth of multiple transplanted tumors, and the effect was significantly stronger than that of single antibody Based on the above obvious functions and a series of subsequent safety evaluation data, as well as CMC and other necessary materials, Hengrui applied to FDA for clinical trial of shr-a1403 in December last year In January this year, Hengrui pharmaceuticals announced that its holding subsidiary, Hengrui therapeutics Inc., in the United States, could carry out clinical trials of shr-a1403 drugs after receiving a written notice from FDA It is the first ADC drug approved by FDA in clinical trials At present, the clinical trial information of shr-a1403 can not be found on clinicaltrials.gov It is speculated that the project is still in the preparation stage From the perspective of indications of drugs under research, it covers a variety of cancers, including gastric cancer, liver cancer and other high-risk cancers in China Therefore, if the drug can be clinically proved to be safe and effective, its market prospect is relatively broad Focus of genneron f-627: the third generation product, but the long-term G-CSF class competition is fierce Phase III clinical results are the key Factor (granulocyte colony stimulating factor) is considered to be the key factor to promote the development and release of neutrophils from the bone marrow It can regulate the early development, survival, migration and activation of neutrophils by activating its receptor Therefore, G-CSF can be used in theory to treat neutropenia caused by various reasons F-627 is a recombinant human g-csf-fc fusion protein, which is expected to be used in the treatment of chemotherapy-induced neutropenia It uses the gemelon bimolecular technology platform to connect the human G-CSF molecule with the FC segment (IgG2 subtype) of the antibody Because FC segment can form dimer through the disulfide bond between chains, a drug molecule contains two G-CSF molecules In fact, recombinant G-CSF protein is not a novel drug target As early as 1991, the FDA approved Amgen's filgrastim, the first generation of recombinant human G-CSF, for the treatment of neutropenia Because of the short half-life of the molecule, it needs to be injected many times after each chemotherapy After that, Amgen modified filgrastim with PEG, and obtained the second generation of recombinant human G-CSF (pegfilgratim, neulasta) (listed in 2002, with a global sales volume of US $4.6 billion in 2016) Its half-life was prolonged, and only one injection was needed after each chemotherapy, but the affinity with G-CSFR was reduced due to PEG modification at N-terminal At present, the long-term recombinant human G-CSF (including Sandoz and coherus products) under research is the second generation of imitation The f-627 of jiannenglong belongs to the third generation In addition to prolonging the half-life of the molecule, the fusion FC can also promote the dimerization of G-CSF by carrying two G-CSF, thus enhancing the activation of downstream signals In the phase I clinical trial completed in Australia in 2011, f-627 showed good safety and pharmacokinetic characteristics; the data of international multicenter phase II clinical trial (the clinical trial in the United States was approved by FDA in May 2012, and the whole trial ended in October 2014) showed that the treatment effect of f-627 was not inferior to that of the control drug neulasta, and the half-life was slightly longer than that of the control drug The international phase III clinical application was approved by FDA in May 2016 The test consists of two parts: gc-627-04 and gc-627-05 Gc-627-04, the first phase, was launched in December last year It is a randomized, multicenter, double-blind trial comparing f-627 with placebo to evaluate the safety and effectiveness of f-627 At present, it has completed the enrollment of patients in many countries in the United States and Europe Gc-627-05 is the second phase, which is a randomized, multicenter, open label test comparing the safety and efficacy of f-627 and control drug neulasta On October 10, jiannenglong received FDA