Genuine Biotech Attended New Drug Innovators Conference, Addressing Antibody-Drug Conjugate (ADC) Resistance Challenges with Novel Non-Camptothecin Toxins

Recently, the 11th Chengdu New Drug Innovators Conference, as part of NDC2026, was successfully held. This conference brought together experts, scholars, and industry representatives in the biopharmaceutical field to jointly discuss cutting-edge R&D achievements and hot topics in the biopharmaceutical industry. Dr. Dang Qun, President of Genuine Biotech, was invited to attend the conference and deliver a presentation titled "Next-Generation Non-Camptothecin TOPO1 Inhibitors Designed for DXD-ADC Resistance by Using Artificial Intelligence Drug Discovery and Design (AIDD)", demonstrating the company's exploration of the novel TOPO1 inhibitor platform in overcoming the existing challenges of tumor resistance.

Focusing on ADC Resistance Challenges: A New-Generation Non-Camptothecin TOPO1 Inhibitor Platform

At present, antibody-drug conjugate (ADC) drugs are rapidly becoming the cornerstone of tumor treatment and reshaping the overall anti-tumor market. Among the payloads of ADCs, TOPO1 inhibitors are one of the most widely used toxins in clinical practice. However, with the widespread application of camptothecin drugs, represented by irinotecan, the emergence of drug resistance has become an inevitable challenge.

Among them, the drug resistance factors directly related to toxins mainly include two aspects: one is the efflux pump mechanism. Many ADC toxins are substrates of breast cancer resistance protein (BCRP), and increased active efflux has become one of the main causes of ADC resistance; the other is target mutation. After clinical treatment with TOPO1 toxin ADC drugs, some patients have been detected with target mutation-related drug resistance. Together, these factors contribute to the disease progression of many patients with tumors after treatment with currently available therapies. In the face of this urgent unmet clinical need, Genuine Biotech focuses on the development of innovative drugs with new structures that can address tumors resistant to existing TOPO1 inhibitors.

According to Dr. Dang Qun, Genuine Biotech has successfully discovered a series of novel TOPO1 inhibitor molecules with new structures by leveraging the AIDD technology to modify the core scaffold. These molecules maintain potent activity against both wild-type and mutant TOPO1. Meanwhile, the optimized molecules effectively overcome the issue that camptothecin toxins are prone to being recognized by efflux pumps, leading to superior intracellular retention of the drug.

PCC molecule ZSSW-136, discovered by Genuine Biotech on this platform, exhibited inhibitory activity in a variety of tumor cell lines in preclinical studies and could effectively inhibit dozens of cancer cells at nanomolar concentrations. In assays employing multiple patient-derived irinotecan-resistant tumor organoids, ZSSW-136 demonstrated 400-fold greater inhibitory activity than irinotecan. More importantly, ZSSW-136 could inhibit tumor growth in irinotecan-resistant tumor PDX animal models.

In terms of safety, myelosuppression is one of the common and noteworthy side effects of irinotecan. Preclinical studies have shown that ZSSW-136 exhibits a more favorable safety profile in normal cells compared with camptothecin analogs.

At present, IND-enabling studies for ZSSW-136 are underway. It provides a novel option to address the drug resistance challenges caused by traditional camptothecin drugs, and is expected to be applied to various XDC (ADC, PDC, SMDC, etc.) conjugate drug programs, providing a new opportunity for the development of novel ADCs effective against existing ADC-resistant tumors.

A Diversified Innovation Platform to Expand the Boundary of Tumor Treatment

Beyond focusing on novel non-camptothecin toxins, Genuine Biotech has built a diversified R&D platform for innovative drugs by drawing on its years of accumulated drug R&D strength. Currently, leveraging its proprietary antibody platform and peptide drug high-throughput screening platform, the company is simultaneously advancing the pipeline development of peptide radionuclide conjugates (PRCs) and ADCs. Targeting innovative oncology targets for which no drugs have yet been approved, it is committed to delivering novel solutions for unmet clinical needs.

According to Dr. Guo Changyue, Senior Vice President of Genuine Biotech and General Manager of its Shenzhen subsidiary, the company focuses on the GRPR target in the field of PRCs. Previous studies have shown that GRPR is expressed at low levels and has a limited distribution in normal tissues, but is highly expressed in a variety of human solid tumors, including lung cancer, breast cancer, prostate cancer, certain gastrointestinal tumors, and neuroblastoma. As it may contribute to tumor growth and progression, GRPR represents a highly promising therapeutic target.

Drugs are being developed for indications such as advanced, metastatic, unresectable tumors and castration-resistant prostate cancer. Traditional treatments achieve limited efficacy and are associated with poor prognosis in such patients, creating an urgent clinical need for more effective therapeutic options. By precisely delivering radionuclides to tumor sites, PRCs enable efficient eradication of lesions while minimizing damage to normal tissues, offering patients novel therapeutic options.

At present, Genuine Biotech has achieved significant progress in this field. The candidate drug ZS-2004 has demonstrated excellent efficacy and safety data in animal studies and is currently under preclinical development.

Dr. Guo Changyue stated that, in ADC R&D, Genuine Biotech has established a dual-payload ADC pipeline targeting PSMA. PSMA is a validated antigen with high tumor specificity, limited normal tissue expression, and efficient internalization. Given the properties of this target, Genuine Biotech has designed a dual-payload ADC featuring an innovative mechanism.

By precisely delivering two toxins with distinct mechanisms of action to tumor cells, this design is intended to simultaneously kill tumor cells in different cell cycles, while targeting both high‑antigen‑expressing and low‑antigen‑expressing subpopulations, thereby addressing the therapeutic challenges arising from tumor heterogeneity. The dual-payload strategy aims to enhance efficacy at the source while delaying or overcoming the risk of drug resistance in a single pathway, so as to provide a more effective and durable response for clinical treatment. The synergy between the two mechanisms of action is also expected to improve the therapeutic index and safety window.

The candidate drug ZS-1005 developed by Genuine Biotech based on this strategy showed excellent tumor growth inhibition and a favorable safety profile in mouse models, such as prostate cancer.

From the development of novel non-camptothecin toxins for overcoming ADC resistance to the comprehensive layout of diversified conjugated drugs centered on ADCs and PRCs, as well as innovative platforms, Genuine Biotech has always adhered to a clinical value-oriented philosophy and focused on unmet medical needs. In the future, the company will continue to advance the R&D of innovative drugs, accelerate the clinical translation of its R&D pipeline, and deliver more treatment options to patients worldwide.