WuXi AppTec 2022-07-05 07:30 Submitted in the United States
Recently, the new anti-tumor drug cadonilimab independently developed by Kangfang Bio has been officially approved for the treatment of recurrent or metastatic cervical cancer. According to public information, this is the world's first approved PD-1/CTLA-4 dual antibody product, and it is also the first approved indigenous bispecific antibody in China. For Kangfang Bio, cardulinizumab is the company's second innovative drug approved for marketing after the PD-1 inhibitor paenoprolizumab.
Dr. Xia Yu, founder, chairman and CEO of Kangfang Biologics, said: "As a new bispecific antibody new drug based on PD-1 immune checkpoints, cardulinizumab can give full play to the synergistic anti-tumor effect of PD-1 and CTLA-4 immune checkpoints, while the side effects are significantly lower than the combination treatment of monoclonal antibodies of the two targets, and the excellent anti-tumor efficacy and safety will bring tangible clinical benefits to the majority of tumor patients around the world." ”
▲Dr. Xia Yu, WuXi AppTec content team
The key to the design of the PD-1/CTLA-4 dual antibody
Speaking of the story of cadonilliumab, the clock is going to be dialed back to before the product was launched. CTLA-4 and PD-1 are known to be the two first targets to develop immune checkpoint inhibitors. But as monotherapy, patient response rates to immune checkpoint inhibitors are limited, which limits their clinical use. Therefore, researchers began to extensively explore the combination of anti-CTLA-4 therapy and anti-PD-1 therapy to improve the efficacy of the synergy between the two. The design of cardulinizumab stems from the enlightenment brought by the exploration of combination therapies.
"Considering some of the toxicity problems in the combination therapy research at that time, it may be due to the undifferentiated binding affinity of antibodies to tumor-infiltrating lymphocytes (TIL) and peripheral site lymphocytes, while PD-1 and CTLA-4 are mainly expressed together in tumor-infiltrating lymphocytes." We thought about how to improve the efficacy of anti-PD-1 monotherapy while solving the problem of toxicity. Dr. Xia Yu, founder, chairman and CEO of Kangfang Biotech, said this earlier when he accepted WuXi AppTec's content team.
Based on these considerations, the KFone bio team designed a tetramer PD-1/CTLA-4 bispecific antibody that can only bind to TIL tetravalents that co-express PD-1 and CTLA-4. This design is not only expected to preserve the efficacy observed in the combination of PD-1 + CTLA-4 inhibitors, but also to reduce the risk of activated T cells attacking healthy tissues, thereby alleviating extra-tumor toxicity.
According to Kangfang Biology, cardulinizumab has four major advantages: 1) it can block the two immune checkpoint pathways of PD-1 and CTLA-4, and its binding ability with PD-1 and CTLA-4 is comparable to that of corresponding single-target antibodies; 2) Fc segment optimization, on the one hand, completely remove the antibody-dependent cell-mediated cytotoxic effect (ADCC)/antibody-dependent cell-mediated phagocytosis (ADCP) effect, and avoid immune adverse reactions caused by Fc-mediated immune cell activation; On the other hand, the antibody-dependent cytokine release (ADCR) effect is reduced, which enables the release of IL-8 to enhance efficacy, and the release of IL-6 to reduce immune-related adverse reactions; 3) The stability is more than 100 times that of natural IgG4, which provides a guarantee for the efficacy of the effect, and does not bind to other IgGs, and the host protein residue is low; 4) Strong anti-tumor activity, especially in advanced cervical cancer.
As a "first-in-class" bispecific antibody new drug, the development of cardulinizumab can be imagined to be difficult. According to Dr. Xia Yu, at first they tested many different combinations at the protein engineering level, and after repeated verification, they successfully designed cardulinizumab. After that, the R&D team solved many challenges in the production of dual antibodies, CMC, analysis and identification, and industrialization.
Dr. Xia Yu has said that cardulinizumab is the world's first PD-1/CTLA-4 dual antibody to enter the clinical stage. With no PD-1/CTLA-4 dual antibody in the clinic worldwide, the choice of the first indication is critical to developing a product with better efficacy and safety than existing therapies. After considering it all, they set their sights on a tumor type that needs to be broken through by tumor immunotherapy - cervical cancer. So, can the Kangfang biological team prove the correctness of this choice in clinical studies?
Clinical data has been recognized by many parties
The answer is yes. According to public information, globally, although anti-PD-1 monoclonal antibodies with indications for the treatment of cervical cancer have been approved for marketing, clinical studies have shown that they have achieved an objective response rate (ORR) of no more than 15% in PD-L1-positive patients above the second line.
At the 2022 American Society of Gynecologic Oncology (SGO) Gynecologic Oncology Annual Meeting, Professor Wu Xiaohua of Fudan University Affiliated Cancer Hospital released the results of the Phase 2 clinical study AK104-201 (cervical cancer cohort) in the form of an oral report on the treatment of cardulinizumab in patients with relapsed or metastatic cervical cancer who had failed platinum-containing chemotherapy. The results showed that the orr of carduinily monotherapy for relapsed or metastatic cervical cancer that had failed platinum-containing chemotherapy, regardless of the patient's PD-L1 status, the ORR of carduinily monotherapy reached 33.0%, and the partial response (CR) rate reached 12%. The ORR of patients treated with PD-L1+ (CPS≥1) was as high as 43.8%. At the same time, the progression-free survival of the treatment group was also significantly improved, and the survival period was also significantly prolonged.
The research results of cardulinizumab in cervical cancer have also been recognized by the regulatory authorities, and have been granted fast-track qualifications and orphan drug qualifications by the US FDA, and have been included in the list of breakthrough treatment varieties by NMPA. In September 2021, Kangfang Biotech announced that it had submitted a marketing application for cadonillizumab for the treatment of recurrent or metastatic cervical cancer, and was included in the priority review by the Drug Evaluation Center (CDE) of the State Food and Drug Administration of China.
Screenshot source: CDE official website
Cervical cancer is the fourth leading cause of cancer death in women worldwide, most commonly diagnosed between the ages of 35 and 44. Almost all cases are caused by human papillomavirus (HPV) infection. Cervical cancer can usually be cured when detected early and effectively managed, but treatment options are limited at an advanced stage of the disease or when the cancer has spread. The approval of cardulinizumab in China means that it is expected to bring better treatment to patients with advanced cervical cancer.
In addition to the approved second- and third-line treatment of cervical cancer, cardulinizumab has also obtained positive data in the first-line treatment of cervical cancer. At the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, the results of an excellent Phase 2 clinical study of carduline combined with platinum-containing chemotherapy +/-bevacizumab in the first-line treatment of recurrent/metastatic cervical cancer have been released. The data show that at a dose of 10 mg/kg, regardless of PD-L1 expression, the ORR of cardulinelli combination therapy was 79.3%; For the cpS ≥1 population, the ORR was 82.4%; For people with CPS <1, the ORR was 75.0%. This data also indicates that cardulinizumab has the potential to fully cover people with recurrent/metastatic cervical cancer.
In addition to cervical cancer, Kangfang Bio is also exploring the therapeutic potential of cardunilizumab in more indications, including lung cancer, liver cancer, stomach cancer, kidney cancer, esophageal squamous cell carcinoma and nasopharyngeal cancer. Among them, the first-line treatment of cardulinizumab for gastric adenocarcinoma/gastroesophageal adenocarcinoma, as well as for neoadjuvant therapy for early-stage hepatocellular carcinoma, have entered registered clinical trials.
It is hoped that cardulinizumab will also progress well in other clinical studies, bringing new treatment options and clinical benefits to more cancer patients as soon as possible.
Resources:
The State Food and Drug Administration conditionally approved the listing of cardulinizumab injection. Retrieved Jun 29 , 2022. From https://www.nmpa.gov.cn/yaowen/ypjgyw/20220629135936153.html
[2] Clinical data on the treatment of Cedunil (PD-1/CTLA-4 dual antibody) in the treatment of R/M cervical cancer Phase II will be reported orally at SGO 2022. Retrieved Mar 16 , 2022. from https://mp.weixin.qq.com/s/ZM-DSz_xSgwN_d3AlImriA
[3] The State Drug Administration accepted the application for the marketing of Kadernin (PD-1/CTLA-4 bispecific antibody) for the treatment of patients with recurrent or metastatic cervical cancer. Retrieved Sep 24 , 2021. from https://mp.weixin.qq.com/s/QzZ9tweeI9Lj83FuqqNOxw
[4] Clinical research results on the progression of metastatic nasopharyngeal carcinoma after treatment of second-line and above chemotherapy by Kangfang Biologics PD-1/CTLA-4 dual antibody (AK104) were released in SITC 2021. Retrieved Nov 15 , 2021. from https://mp.weixin.qq.com/s/g1-cX9dEz7EndpMYjUshGQ