Recently, the combination antibody of apalutamide toripalimab (QL1706, trade name: Qilu'an, hereinafter referred to as "etuo combination antibody") has been approved by the National Medical Products Administration (NMPA) of China for the treatment of recurrent or metastatic (R/M) cervical cancer patients who have failed platinum-based therapy. This milestone development not only signifies a major breakthrough in the treatment of advanced cervical cancer in China, but also heralds a new stage of development for cancer immunotherapy.It is reported that the Etu combination antibody is the first dual-function combination antibody targeting PD-1 and CTLA-4 designed and produced by Qilu Pharmaceutical through its self-developed MabPair®️ technology platform.

It has shown great potential in the treatment of solid tumors such as cervical cancer, lung cancer, and liver cancer, demonstrating both efficacy and safety. With its unique mechanism, it is at the forefront of the journey of tumor dual immunotherapy strategy!Cervical cancer is the fourth most common cancer among women worldwide and a leading cause of cancer-related deaths in women. For patients with cervical cancer who have failed first-line treatment, there is an urgent need for safe and effective clinical treatment options. As the world's first dual-function combination antibody targeting PD-1 & CTLA-4 to apply for market approval, the Atezolizumab combination antibody can target and inhibit two immune checkpoint pathways (anti-PD-1 IgG4 and anti-CTLA-4 IgG1) with good safety profile, showing preliminary efficacy in cervical cancer patients in early studies.

The approval of Atezolizumab combination antibody for the second-line and above treatment indication in recurrent or metastatic (R/M) cervical cancer is mainly based on the key registration study data in R/M cervical cancer patients (DUBHE-C-206 study). In this multicenter, open-label, single-arm, phase II trial, 148 R/M cervical cancer patients who had failed first-line platinum-based chemotherapy (± bevacizumab) and had not received prior immunotherapy were treated with Atezolizumab combination antibody (5mg/kg Q3W).

As of October 28, 2023, with a median follow-up of 17.5 months, the objective response rate (ORR) was 33.3%, the median progression-free survival (PFS) was 5.4 months, and the median overall survival (OS) reached 17.1 months. In terms of safety, the incidence of grade ≥3 treatment-related adverse events (TRAE) with Atezolizumab combination antibody was 27.0%, with only 3.4% of patients discontinuing treatment due to TRAE, and no treatment-related deaths occurred. Historical data from studies on immunotherapy for advanced cervical cancer show that the efficacy of Atezolizumab combination antibody is superior to single immune checkpoint inhibitors, and the rate of severe adverse events is comparable to PD-1 monotherapy and significantly lower than approved dual immunotherapy drugs. The approval of Atezolizumab combination antibody provides a new treatment option for this patient population, not only improving their survival rates but also potentially enhancing their quality of life.

The significant efficacy and good safety profile of the atezolizumab combination therapy in the salvage treatment of cervical cancer have also propelled its exploration in first-line treatment. The DUBHE-C-204 study is an open-label, multicenter, non-randomized phase II study aimed at evaluating the efficacy and safety of atezolizumab combination therapy with or without bevacizumab in first-line treatment of R/M cervical cancer (without restriction on PD-L1 expression levels). Results showed that with a median follow-up of 14.0 months, the ORR reached 81% (95% CI, 68.6%-90.1%), with a complete response (CR) rate of 10.3% and a disease control rate (DCR) of 98.3% (95% CI, 90.8%-100.00%); the median PFS was 14.3 months (95% CI, 9.2 months-NE).

The results of the DUBHE-C-204 study confirmed the significant benefit of atezolizumab combination therapy in first-line treatment of R/M cervical cancer, with benefits observed regardless of the patients' PD-L1CPS status. This data, compared to previous studies on immunotherapy combinations, further enhances the benefits for patients and injects strong momentum into the exploration of atezolizumab combination therapy in the field of cervical cancer. Building on this, a phase III clinical trial (DUBHY-C-308) of atezolizumab combination therapy in first-line treatment of R/M cervical cancer is currently underway. The study has completed enrollment, and the results are expected to provide more robust evidence for the application of atezolizumab combination therapy in the field of cervical cancer.Looking back to 2015, when immune checkpoint inhibitors PD-1 monoclonal antibody and PD-L1 monoclonal antibody were just approved, the entire industry was excited. The R&D team at Qilu Pharmaceuticals was eager to develop more effective products, especially multi-functional and multi-target products, to meet urgent medical needs. It can be said that the birth of the MabPair®️ technology platform is an innovative achievement for Qilu Pharmaceuticals after years of dedication to antibody engineering.

The core value of the MabPair®️ technology platform lies in its ability to produce two different monoclonal antibodies from a single cell line. Compared to conventional bispecific antibody platforms, MabPair®️ products are structurally closer to natural antibodies and can be further optimized for product function and efficacy by adjusting the ratio configuration between antibodies and introducing uniquely designed heavy chain pairing keys and light chain pairing keys to prevent antibody mispairing. A combination antibody called Aito, nurtured by the MabPair®️ technology platform, has laid a solid foundation for the development of this platform. The CTLA-4 monoclonal antibody in the Aito combination antibody uses the IgG1 subtype, retaining antibody-dependent cell-mediated cytotoxicity (ADCC) effect.

After binding to regulatory T cells with high CTLA-4 expression, it triggers the ADCC effect, killing regulatory T cells and enhancing the anti-tumor effect. The CTLA-4 monoclonal antibody has been Fc-modified to shorten the half-life to one week, reducing the risk of adverse reactions that may occur due to prolonged CTLA-4 inhibition. The anti-PD-1 part adopts the more mainstream IgG4 framework, avoiding ADCC and complement-dependent cytotoxicity (CDC) effects, helping to maintain the long-term survival and function of T cells, thereby enhancing the tumor-killing ability of T cells.