Tianshu Star Shines at ESMO: Professors Shi Benkang and Jiang Xuewen Highlight Qilu's Aito Bispecific Antibody as a Promising 'Highly Effective, Low-Toxicity' Strategy for Precision RCC Therapy

Over the past decade, ICIs have been gradually applied in the treatment of RCC. The Phase III clinical trial CheckMate 025 established the role of ICIs in the treatment of advanced renal cell carcinoma. In terms of adjuvant therapy, several key Phase III studies have been conducted. Only the KEYNOTE-564 study found that ICIs monotherapy can improve DFS and OS in patients with intermediate to high risk of RCC recurrence. Other studies, such as the PROSPER study, did not yield positive results. Therefore, further exploration and attempts are still needed in the field of adjuvant therapy.

In the comprehensive treatment of advanced renal cell carcinoma, CheckMate 214 is a landmark international Phase III clinical trial. The study results showed that in IMDC intermediate- and poor-risk patients, nivolumab combined with ipilimumab significantly prolonged median progression-free survival (PFS) and overall survival (OS) compared to sunitinib. However, in the IMDC favorable-risk population, the objective response rate (ORR) and median PFS of the combination regimen were lower than those of sunitinib, showing less efficacy than targeted therapy, and there was no significant difference in median OS between the two groups.

Based on the existing evidence, the combination of PD-1/PD-L1 inhibitors with CTLA-4 inhibitors has shown promising potential in the treatment of renal cell carcinoma (RCC), and novel combination strategies are still under continuous exploration. Currently, research on multiple immune checkpoint inhibitor (ICI) combination regimens mainly focuses on advanced or metastatic RCC, or for first-line and subsequent treatments when monotherapy proves ineffective. To date, only the combination of nivolumab and ipilimumab has received a Class IA recommendation. Although multi-immunotherapy combinations demonstrate significant prospects for application, the complexity of the immune system may lead to unpredictable immune-related adverse events (irAEs). In addition to symptomatic support treatment using steroids, how to mitigate irAEs and regulate the excessive release of cytokines will become key directions for future research.

Through previous research, we found that the combination of PD-1 inhibitors and CTLA-4 inhibitors is an effective treatment for metastatic clear cell renal cell carcinoma (mccRCC). Based on this, we conducted a Phase Ib study on the tolerability, safety, and preliminary efficacy of the Aito combination antibody plus lenvatinib in patients with advanced renal cell carcinoma. The study data was重磅 released during the 2025 ESMO Congress.

The study results showed that, in terms of efficacy, with a median follow-up time of 22 months, the objective response rate (ORR) was as high as 75.0% among 20 evaluable patients, and the disease control rate (DCR) was 90.0%. The PFS rate at 22 months was 54.4%, with a maturity of 35%. Although the median duration of response (mDOR), PFS, and OS have not yet been reached, the PFS is expected to exceed 21 months.

In terms of safety, although almost all patients experienced treatment-related adverse events (TRAEs), the incidence of TRAEs of grade ≥3 was 65.0%, with most being dominated by lenvatinib-related toxicities, such as hypertension (39.4%) and palmar-plantar erythrodysesthesia syndrome (15.2%), which are familiar to clinicians and manageable. No treatment-related deaths occurred in the study. Meanwhile, the safety data of the subgroups were consistent with the overall population.

The combination of PD-1 and CTLA-4 antibodies, while enhancing efficacy, also brings a certain risk of high toxicity. The development of the Aito combination antibody addresses this issue by utilizing its proprietary MabPair technology.^®Antibody Patent Platform: Targeted Optimization at Three Levels

Golden Ratio, Precise Synergy: Traditional combinations simply superimpose two drugs with uncontrollable ratios. QL1706 simultaneously produces two antibodies in a single cell, fixing them at the golden ratio of anti-PD-1:anti-CTLA-4 ≈ 2:1. This design aims to maximize synergistic effects while avoiding systemic toxicity caused by CTLA-4 antibody overexpression, pursuing high efficacy and low toxicity from the "formulation" source.

Short-acting CTLA-4, Skillfully Controlling Toxicity: The Essence of QL1706 Design. Researchers modified the Fc segment of the CTLA-4 antibody (Tovorali monoclonal antibody), reducing its binding affinity with FcRn (neonatal Fc receptor, a key receptor for prolonging antibody half-life). This shortens the half-life of the CTLA-4 antibody in the body from the traditional 2-3 weeks to about 1 week. This means that after rapid onset, it can be cleared more quickly, significantly reducing persistent immune activation, thereby systemically lowering the risk and severity of irAEs.

High-efficiency PD-1, Retaining Activity: The PD-1 antibody (Aipalolizumab) uses the IgG4 subtype, eliminating ADCC/CDC effects to avoid killing T cells that possess anti-tumor activity. Meanwhile, the CTLA-4 antibody adopts the IgG1 subtype while retaining its ADCC effect, effectively depleting regulatory T cells (Tregs) in the tumor microenvironment, "unlocking" immunosuppression and clearing obstacles for T cells to attack tumors.

Selection of First-Line Treatment for Renal Cell Carcinoma Requires Individualized Decision-Making Based on Multidimensional Factors

Atezolizumab Combination Antibody as a Novel Immunotherapy Drug: Based on the preliminary evidence of its combination with Lenvatinib for first-line treatment of renal cell carcinoma, this combination regimen may offer potential advantages in specific patient populations. For patients with intermediate- to high-risk IMDC classification, high tumor burden, or sarcomatoid differentiation, Atezolizumab Combination Antibody may enhance anti-tumor effects by activating immune responses and synergizing with Lenvatinib's anti-angiogenic activity. Additionally, if patients exhibit molecular features of an immune-active phenotype, such as high infiltration of T-effector cells, this combination therapy may also exert synergistic effects, further improving prognosis.

With the improvement of long-term follow-up data from relevant studies and the launch of more clinical trials, the treatment strategy of Aito combination antibody plus Lenvatinib is expected to expand into other application scenarios, such as neoadjuvant therapy for early-stage patients, adjuvant therapy for high-risk recurrent RCC patients, late-line salvage therapy for advanced cases, and even rare subtypes like non-clear cell renal carcinoma, thereby advancing kidney cancer treatment towards a more precise and safer direction.

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