2020 was a year of COVID-19’s wreak havoc, and also a year of rapid growth in biomedicine. We recorded the development of the industry news.
Popular targets
PD-1
Although PD-1 has been on the market for many years, research on its mechanism is still deepening, including complex cis interactions. In September 2020, Science Advances published a systematic review of the PD-1 pathway by scientists from Harvard Medical School.
The research group of Liao Xuebin and Hu Xiaoyu of Tsinghua University found that KDM5A and PD-1 antibody had a synergistic effect.
Chinese scientist Chuan-yuan Li of Duke University Medical Center published an article in Nature and found that inhibiting PCSK9 antibody can enhance the anti-tumor effect of PD-1 antibody.
PAK4 inhibitors have been found to have a synergistic effect in combination with PD-1, and the combination with CAR-T was expected to treat solid tumors. The mechanism was PAK4 inhibitors can reshape the vascular morphology of tumor tissues and facilitate the infiltration of T cells.
CD47
This year is the year when CD47 has fully turned into heat. At the end of 2019, FortySeven announced the positive clinical data of CD47 antibodies at the ASH conference, rectifying the name of the CD47 target. This field quickly attracted many multinational pharmaceutical companies in 2020. Gilead acquired Fortyseven for US$4.9 billion, AbbVie and Tianjing Biotechnology reached a US$3 billion cooperation, and Pfizer made a strategic investment in Trillium.
In addition to antibodies, SIRPα fusion proteins have also attracted many domestic pharmaceutical companies. Hengrui has taken a unique approach and developed SIRPγ-based PD-L1/CD47 double antibodies.
Immunity published an article to conduct in-depth research on the mechanism of SIRPα-CD47 pathway, which was quite enlightening. Japanese scientists invented SIRPα macrocyclic peptide blockers.
Claudin 18.2
Claudin 18.2 and CD47 are the most competitive targets in China after PD-1. Mainly because Claudin 18.2 is used for gastric cancer, it is a high-incidence type of cancer in China. Therefore, it has become a battleground for domestic pharmaceutical companies. Around this target, ADCC enhanced monoclonal antibodies, ADCs, double antibodies, CAR-T, etc. emerge in endlessly. BioNtech’s mRNA therapy (expressing Claudin 18.2 antibody) has entered the clinical stage.
Complement
At the end of 2020, AstraZeneca acquired Alexion for US$39.4 billion, once again bringing Complement-targeted therapeutics to the stage. The complement field has also made a lot of progress in recent years. Apellis’ C3-targeting cyclic peptide drug APL-2 has been submitted to the FDA for marketing application, and its clinical effect was completely better than Soliris. Sobi and Apellis reached a US$1.2 billion partnership to jointly develop APL-2. Sanofi C1s antibody has already submitted a listing application, but the listing will be delayed due to the receipt of CRL due to production problems. C5aR small molecule inhibitor CCX168 has been submitted for listing application, and Tianjing Bio’s C5aR antibody has been submitted for clinical trial application.
Clotting factor
Sanofi’s recombined eight-factor BIVV001 once a week has been applied for clinical application in China, and FXI antibody and TFPI antibody have also attracted some pharmaceutical companies. FIX/FX bi-antibody Hemlibra of Roche/Chugai Pharmaceutical is expected to surpass eight factors soon and become the best-selling hemophilia drug. Chugai is developing a second-generation FIX/FX bi-antibody (non-common light chain), Novo Nordisk etc. are also developing similar drugs.
Self-immune new target
AstraZeneca’s TSLP antibody treatment of asthma and IFNAR1 antibody treatment of lupus are two phase III clinical trials with one success result and one failure result. It is still unknown whether they can be approved.
GLP-1
In 2017, liraglutide became the first GLP-1 to enter medical insurance, and the GLP-1 market has risen. In the medical insurance negotiations at the end of 2020, a number of GLP-1s were successfully entered, including dulaglutide, loxenatide, exenatide, benaglutide, and lixisenatide.
After dulaglutide and semaglutide, GLP-1, GCG, and GIP multi-target agonists have become new directions for exploration. Eli Lilly’s GLP-1/GIP dual target agonist has achieved its first phase III clinical success. In addition, new indications are also the direction of GLP-1. Semaglutide has already initiated Phase III clinical trials for Alzheimer’s disease. Dulaglutide initiates a phase II clinical trial (initiated by a non-pharmaceutical company) that affects male sexual function. Some pharmaceutical companies are making new differentiations. For example, Pfizer has developed a small molecule GLP-1 receptor agonist, which has excellent early clinical data.
ADC
In the past year or so, the ADC drug field has reached over 40 billion US dollars of transactions, and many multinational pharmaceutical companies have deployed. ROR1, HER2, Trop2, etc. are popular ADC drug targets.
Merck & Co/VelosBio’s ROR1 targeted ADC drug released promising early clinical data at the ASH meeting. The overall response rate of MCL was 47% (7/15), including 3 cases of CR and 4 cases of PR. The overall response rate of DLBCL was 80% (4/5), including 2 cases of CR and 2 cases of PR.
Bolt developed ISAC technology, antibody conjugated TLR7/8 agonist. Silverback has developed ImmunoTAC technology, antibody conjugated TLR8 agonist. Sutro couples TLR agonists and toxins to antibodies at the same time, and its activity is significantly stronger than ISAC.
AbbVie continues to lay out ADC drugs for autoimmune diseases, coupling hormones to TNFα antibodies, and directing hormones to inflammatory tissues through antibodies to avoid the side effects of hormone system administration.
Zhejiang Pharmaceutical Group/Ambrx’s targeted HER2 ADC drug ARX788 has obtained very beautiful data. The first-stage clinical disease control rate is 100%, and DS-8201 is still effective after drug resistance.
Hillhouse Capital’s Lead Pharmaceuticals introduced four ADC drugs from ADC Therapeutics for US$50 million.
Target biology research is getting deeper and deeper
The Fc effector effect of TIGIT antibody is intuitive and important. The research group of Jianhua Sui of Beisheng Institute discussed the specific mechanism in an article in Journal of Immunology. The combination of Roche’s TIGIT antibody and PD-L1 antibody has obtained good data, but single-agent therapy is ineffective. TIGIT is also the first echelon of pharmaceutical companies such as Hengrui Pharmaceuticals, BeiGene, Cinda Biologicals, and Junshi Biologicals to compete in the layout target. TIGIT is also another target for the first-echelon pharmaceutical companies such as Hengrui Pharmaceuticals, BeiGene, Cinda Biologicals, and Junshi Biologicals to compete in the PD-1 pathway.
The mechanism of action of immune checkpoint agonist antibodies is more complicated than that of inhibitor antibodies. Epitopes, valence, cross-linking, affinity, etc. all have a significant impact on the activation effect. Taking CD40 as an example, Apexigen’s APX-005M introduced S267E to enhance FcγRIIB-mediated cross-linking. Scientists from the University of Southampton mentioned in the Cancer Cell article that replacing the IgG2 subtype can convert multiple CD40 inhibitor antibodies into agonist antibodies, and found that the flexibility of the hinge region determined whether it had agonist activity.
Siglec-15, the clinical failure of NextCure, terminated the NSCLC monotherapy. In an article published by NEJM in October, the Phase II clinical trial of Siglec-8 antibody AK002 for the treatment of cytophilic gastritis and duodenitis was successful.
Antibody subcutaneous injection
Subcutaneous injection can often make administration more convenient and faster. Halozyme’s hyaluronidase technology can increase the volume of subcutaneous administration and has been successfully used in many antibody drugs such as Roche’s rituximab, trastuzumab, Johnson & Johnson’s Daratumumab, etc. Shanghai Pharmaceuticals has also adopted a similar technology, applying for a CD20 antibody subcutaneous injection, and hyaluronidase is from Kangju Biotechnology.
Sugar engineering
Daiichi Sankyo introduced the sugar engineering technology license of GlycoT Therapeutics. The founder of the company was Dr. Wang Laixi, a Chinese scientist. He used the in vitro enzymatic reaction to directionally modify the glycoforms and modify the Fc effector effect. It can also achieve targeted coupling of ADCs through sugar.
Antibody drugs
By the end of 2020, the FDA has approved a total of 99 antibody drugs, which will soon reach triple digits. The medical notes sorted out the antibody drug pipelines of dozens of domestic pharmaceutical companies.
Connoa, Deqi Pharmaceuticals, Hobo Pharma, WuXi Biologics, Zai Lab, Biocytogen, CStone Pharmaceuticals, BeiGene, Cinda Biologicals, Junshi Biologicals, Hengrui Pharmaceuticals, Zhongshan Kangfang, Jiahe Biologicals , Zhidao Biology, Daoer Biology, Shangjian Biology, Lijin Biology, Kangqiao Capital, Yu Guoliang, Quanxin Biology, Immune-Onc, Anyuan Medicine, Sansheng Guojian, Renhui Biology, Lepu Biology, Immune Onco , Paige Biologics, Maiwei Biologics, Momenta, Betta Pharmaceuticals, Zejing Pharmaceuticals, Hausen Pharmaceuticals, Huahai Pharmaceuticals, Kelun Pharmaceuticals and Vanessa.
Double antibody
In June 2020, Cinda Bio introduced Roche’s 2:1 TCB double antibody, and many pharmaceutical companies such as Hengrui Pharmaceutical, WuXi Biologics, Tianguangshi, Hobo Pharmaceutical, and Youzhiyou quickly followed up. IgM Bioscience has developed an IgM subtype CD3/CD20 double antibody with a ratio of 10:1, which is more active than 2:1 TCB.
In addition to double antibodies, there are many companies that are developing trispecific antibodies, such as Novartis’s development of CD3/CD2/TAA tertiary antibodies, and Enmu Bio’s development of CD3/CD19/CD20 tertiary antibodies. Bailey Pharmaceuticals has developed PD-L1/CD3/4-1BB/TAA four antibodies. Chugai Pharmaceutical and Sanofi are focusing on the development of CD28/TAA or 4-1BB/TAA co-stimulatory double antibodies, which are combined with CD3/TAA double antibodies or other tumor immunotherapies.
Bristol-Myers Squibb and Agenus’ PD-1+CTLA-4 combination therapy has made a series of progress. Zhongshankangfang’s PD-1/CTLA-4 dual anti-AK104 has achieved the best data in early clinical trials of cervical cancer and dMMR, and the effect is significant better than the historical data of PD-1+CTLA-4 combination.
Johnson & Johnson’s EGFR/cMET dual antibody has submitted a listing application.
Roche’s VEGF/Ang2 double antibody was clinically successful in Phase III, achieving non-inferiority compared with Eylea, and the administration period was extended to 16 weeks.
Pre-antibody
Cytomx, Tianyan Pharmaceutical, BioAtla, Chinese and foreign companies are based on enzyme digestion or ATP bridging. Cheery Biolabs and Revitope have developed a half-antibody-based CD3 double antibody technology. Junshi Bio and Revitope have reached a cooperation to use their technology to develop five double antibody drugs. Amgen has developed a new type of pre-antibody CD3 double antibody, which is fused with CD3 to avoid binding by T cells. CD3 antibodies will be released only after CD3 is cut off in the tumor microenvironment.
IL-2: Hengrui Medicine, Cinda Bio developed the IL-2, Jun Chi Road from real biological organisms and Anwita introduction of two IL-2.
IL-10: Eli Lilly’s $1.6 billion acquisition of AEMO’s PEGylated IL-10 pancreatic cancer phase III clinical was failure. Ding Fu Target developed an EGFR antibody fusion IL-10. In September 2020, Science Signaling published an article by a British scientist, inventing a modified biased IL-10, which improved the affinity of IL-10Rβ and had stronger activity.
IL-18: In June 2020, Nature published an article about IL-18, Aaron M. Ring is the corresponding author, and Dr. Zhou Ting is the first author (has returned to China and joined West Lake University to teach).
Nucleic acid drugs
Novartis PCSK9 siRNA therapy has been approved by the European Union. Although the FDA has been delayed due to production verification issues, the approval is expected to be imminent. Ruibo Biology has submitted a prospectus on the Science and Technology Innovation Board and will become the first domestic small nucleic acid drug.
Summary
The biomedical industry is undergoing rapid development, but it is also facing many challenges. For the domestic biomedical industry, both a deep technical understanding and a keen market sense are needed. In the context of serious homogeneity, seeking innovation and change is the only way. 2021 will still witness more new changes and new trends.