- the first domestically produced dual antibody approved for marketing -
Recently, the State Food and Drug Administration conditionally approved Kangfang Pharmaceutical Co., Ltd. cardenilimab injection (commodity) through the priority review and approval process Name: Caitani) is on the market. This drug is an innovative bispecific antibody independently developed in my country. is suitable for the treatment of patients with recurrent or metastatic cervical cancer who have failed platinum-containing chemotherapy in the past.
Cardenilimab injection is a bispecific antibody targeting human PD-1 and CTLA-4, which can block PD-1 and CTLA-4 and their ligands PD-L1/PD-L2 and B7. 1/B7.2 interaction, thereby blocking the immunosuppressive response of the PD-1 and CTLA-4 signaling pathways, promoting tumor-specific T cell immune activation, and thus exerting anti-tumor effects. The listing of
Cardunelli has many representative meanings. First of all, this is the world's first PD-1/CTLA-4 dual antibody , from O+Y (nivolumab + ipilimumab) and D+T (nivolumab + Treme) Dual-immune combination regimens to PD-1/CTLA-4 dual antibodies have all verified the synergistic anti-tumor effect brought about by PD-(L)1 target and CTLA-4 target blockade. Secondly, is the first domestically produced dual antibody to be approved for marketing in China. It is also an innovative oncology drug that enjoys the priority review and approval process and is launched based on a phase II single-arm trial.
On June 20, CDE issued a notice on the public solicitation of opinions on the " Single-Arm Clinical Trial Applicability Technical Guidelines for Supporting Anti-tumor Drug Marketing Applications" , the population selection for single-arm studies, cancer types The selection and evaluation indicators have been clearly defined. After reflection on the frequent use of ORR to evaluate research results, it is now necessary to further combine the comprehensive evaluation with other indicators, and also mention the longer-term PFS indicator. Cancer types that can apply for breakthrough therapies and enjoy the fast-track review process also emphasize the need to communicate with CDE in advance. Based on the above two points, it can be predicted that the R&D track of innovative drugs will gradually become more standardized and stricter. The registered indication of bio's cardunirimab was for recurrent or metastatic cervical cancer that failed to be treated with platinum-containing chemotherapy. It adopted a single-arm study design and the study endpoint was ORR. fully enjoyed the policy dividend and obtained accelerated approval. After introducing the first domestically produced dual antibody, let’s review the current situation of the world’s first dual antibody. .
- the world's first dual antibody to turn red -
The world's first dual antibody product - catumaxomab , which was of epoch-making significance, targets CD3 and EpCAM. The initial indication is malignant. I had ascites, but I was born at the wrong time. At that time, immune checkpoint inhibitors were just starting to show off, and they were not as popular as I am now. They were eventually withdrawn from the market in 2017 due to unfavorable commercial promotion. .
In view of the great development of immune checkpoint inhibitors in recent years, immune tolerance and immune enhancement anti-tumor, there are not many gaps to fill. As the world's first dual antibody, the two targets can be effective. It plays a bridging role between T cells and tumor cells and is undoubtedly a potential product for tumor treatment. In China, focuses on advanced gastric cancer with peritoneal metastasis.
Catumaxomab is epoch-making from my perspective. The significance is not only that it is the world's first dual antibody, but also the selection of indications and the choice of intraperitoneal infusion are inspiring for the development of dual antibodies. The design of
dual antibody breaks through the target selection of
dual antibody in solid tumors. Before the discovery of immune checkpoints, one of the commonly used targets was CD3. Since the CD3 target is widely expressed on T cells, excessive stimulation can cause damage to normal organs and tissues. Therefore, for dual antibodies with CD3 as the base target, the other target is generally a target that is highly expressed on tumor cells.In the past, CD19, CD20, etc. on blood tumor cells were basically used, which can narrow the distance between T cells and blood tumor cells in blood vessels to achieve a targeted elimination effect. In addition, the half-life of of dual-antibodies is generally . Compared with solid tumors, the dual antibody has a higher safety profile in hematological tumors than in solid tumors. And if dual antibodies cannot achieve a breakthrough in solid tumors, the prospects will naturally be bleak.
Catumaxomab's CD3 target partner is EpCAM, which is positively expressed in more than 80% of gastric cancer patients. The administration method used is intraperitoneal infusion to maximize the tumor enrichment effect. Of course, these innovations often have unpredictable difficulties. Among the secondary endpoints of its study, I also saw the following two points: the pharmacokinetic parameters of catumaxomab in plasma by intraperitoneal infusion of , and the incidence of anti-drug antibodies of catumaxomab in serum. Comparing the two phases of
, we need to be cautious in selecting the target of dual antibodies. Choosing a target combination that has already been used as a monoclonal antibody drug has relatively low risk in developing a drug. However, the choice of cancer types is naturally limited. And it is necessary to compare the dual-immune combination program, whether it is head-to-head or historical comparison. If dual-antibody wants to gain more markets, it must prove what its advantages are compared to the dual-immune combination program. Secondly, selecting potential targets, such as Claudin18.2, Her3, and EpCAM, how to select another partner target, and how druggable the own target is are also issues. Here is another example, that is Her2/Her2 double antibodies, double antibodies with different binding epitopes of Her2, such as ZW25, how to PK the unstoppable third-generation ADC DS-8201 in the fields of gastric cancer and breast cancer . It is already difficult to achieve an indication breakthrough. At the 2022 ASCO conference, DS-8201 also achieved positive results in people with low expression of Her2. The evolution of HER2's evaluation criteria is similar to the evolution of PD-L1's evaluation criteria from TPS to CPS to an unknown future. How to better serve one's own products and better obtain indication coverage for the population is one of the cores of medical design. This article will not elaborate on this point as it has been mentioned in many articles in the past.
- The way to break the situation in the era of tumor immunity 2.0 -
These are real examples. For institutions that are chasing investment return ratio, in the field of innovative drugs, they should be less desperate and focus more on more successful experimental directions. layout. Let’s take the tumor immunity track led by PD-1 as an example. The main entry points are summarized:
- uses anti-PD-(L1) monoclonal antibodies combined with radiotherapy, chemotherapy, targeted therapy, etc. to explore indications. At present, the immune combination regimen has rewritten the standard treatment regimen for many tumors.
- is exploring other potential drug targets, but single-drug treatments for immune checkpoints such as LAG3 and TIGIT have limited effects. Currently, attempts are being made to expand indications in combination with anti-PD-1 monoclonal antibodies.
- In addition to focusing on immune checkpoints, many companies have begun to focus on the research and development of T cell agonists, including antibodies targeting OX40, CD27, CD40, GITR and 4-1BB. However, due to toxicity issues, the progress of agonists is slower than that of immune checkpoint inhibitors, and no drugs have yet been approved for marketing.
- uses PD-(L)1 as the basic target to iteratively upgrade dual-antibody and multi-antibody technology, such as PD-1/CTLA-4, PD-L1/CTLA-4 and other dual immune checkpoint dual antibodies. There are also companies in the layout PD-L1/4-1BB immune checkpoint combined with dual antibodies against agonistic sites.
With the approval of cardunirumab, competition on the dual-antibody track will inevitably intensify. However, in view of the past excessive involution of anti-PD-1 monoclonal antibodies and the brutal price war, On April 11, 2022, CDE released the "Technical Guidance Principles for the Clinical Research and Development of Bispecific Antibody Anti-tumor Drugs (Draft for Comment)", Seek opinions from the industry. Practitioners of dual-antibodies have put forward higher requirements . How to effectively make up for the clinical needs that immune monoclonal antibody drugs cannot meet, and whether the target selection is reasonable are all issues that need to be solved urgently.
Immune checkpoint dual antibodies are not a random combination
On May 5, 2022, the American technology company Xencor announced its financial report for the first quarter of 2022. What caught my attention was that in its pipeline, some dual antibodies with relatively focused targets announced their progress.
Tidutamab (SSTR2 x CD3) and Neither program demonstrated competitive clinical characteristics in recent trials, and the company has decided to focus its resources on new clinical programs. The company will continue to support currently enrolled and treated patients.
Vudalimab (PD-1 x CTLA-4) : Xencor is supporting two newly initiated investigator-sponsored studies of Vudalimab in patients with advanced cholangiocarcinoma and in patients with advanced rare cancers.
Judging from XmAb841 and Vudalimab, both are relatively mature immune checkpoints: PD-1, LAG-3, CTLA-4. Why did choose CTLA-4 x LAG-3 instead of the already existing dual-immunity combination regimen? What about the indication-approved PD-1 and LAG-3 as dual antibody targets? Maybe the layout of is too early, and the choice of target is naturally like making a bet. This is also a hurdle that companies with a dual-resistance layout cannot get around.
also allows us to see that dual antibodies are not a simple overlapping of targets, and dual antibodies are not a new thing. The earliest concept can be traced back to the 1960s. After such a long time, up to now, the dual antibody products approved for marketing, There are only about 6 models. And in view of its unique PK and PD characteristics, there are fewer dual antibodies for tumor indications, and most of them are hematological tumors. In the field of solid tumors, dual antibodies still have a long way to go.
