Genuine Biotech's Non-Camptothecin Toxin Presented at CBI2026, Breaking the Antibody-Drug Conjugate (ADC) Resistance Bottleneck

Recently, the CBI2026 Biopharmaceutical Innovation Expo concluded in Suzhou, with an exhibition area of over 36,000 square meters and more than 20,000 on-site attendees jointly fostering a new industrial ecosystem. The conference featured multiple parallel forums. At the session "ADC New Drug Discovery and Front-End Technology Innovation", Dr. Dang Qun, President of Genuine Biotech, shared the latest achievements of the company's novel non-camptothecin topoisomerase I (TOPO1) inhibitor platform in addressing antibody-drug conjugate (ADC) resistance. 

Precision treatment modalities exemplified by next-generation ADC drugs are reshaping the cancer treatment landscape, with TOPO1 inhibitor payloads being the most widely used in clinical practice. However, with the widespread use of these drugs, target mutations associated with TOPO1 inhibitor payloads and efflux pump-mediated resistance have become increasingly prominent, and cross-resistance has emerged among ADCs with different antibodies, becoming a key bottleneck hindering improvements in efficacy.

Since the discovery of camptothecin in 1966, the core scaffold of camptothecin-based TOPO1 inhibitors has remained unchanged for more than 60 years. In the face of resistance to existing payloads, could the discovery of next-generation TOPO1 inhibitors help overcome this challenge? Genuine Biotech has conducted in-depth research in this area.

Genuine Biotech successfully replaced one of the five rings in the core scaffold of camptothecin through its self-developed AI-assisted computer-aided drug design (CADD) method, leading to the discovery of next-generation innovative TOPO1 inhibitors and a novel ADC payload platform.

At the beginning of the design, the R&D team fully considered the structural characteristics of the camptothecin core scaffold. AI-driven drug design (AIDD) modeling showed that the R364H mutation shortens residue 364, resulting in the loss of a key hydrogen bond to the nitrogen atom in the B ring of the camptothecin core. This issue also exists in existing camptothecin-based TOPO1 inhibitors.

In order to effectively target the mutant R364H residue, the team replaced the nitrogen atom in the B ring with a longer hydrogen-bond acceptor (a ketone group) and redesigned the core scaffold. AIDD molecular modeling demonstrated that the novel TOPO1 inhibitor can maintain strong hydrogen-bonding interactions with both the wild-type and mutant R364H residues of TOPO1.

In addition, BCRP-mediated drug efflux often causes resistance to many chemotherapy drugs. To address this issue, the team used AIDD modeling for lead optimization to guide compound selection. The modeling results showed that the introduction of a conformational restriction could prevent the BCRP nucleotide-binding domain from transitioning from an open to a closed conformation, thereby reducing the compound's BCRP substrate activity and avoiding active clearance of the drug by the efflux pump at the source.

ZSSW-136 is the first small-molecule PCC compound discovered on this platform and has unique advantages in overcoming resistance to common antitumor drugs. Preclinical studies showed that ZSSW-136 exhibited broad-spectrum antitumor activity in vitro and was not a BCRP substrate. In a primary resistance organoid model, its inhibitory effect on irinotecan-resistant human cancer organoids was 400 times that of irinotecan; in an acquired resistance organoid model, the antitumor activity of ZSSW-136 was 50–180 times higher than that of irinotecan. The results of preclinical in vivo studies in patient-derived xenograft (PDX) models showed that ZSSW-136 at doses of 0.5 and 1 mpk had significant inhibitory effects on tumor growth in irinotecan-resistant intestinal cancer and etoposide-resistant small cell lung cancer models.

In terms of safety, ZSSW-136 also performed well. In the preclinical evaluation of CD34+ hematopoietic stem cell toxicity, ZSSW-136 was 3.2 times safer than the existing camptothecin-based payload DXd, indicating a wider safety window.

At present, the company has built a global intellectual property portfolio around its non-camptothecin TOPO1 inhibitor technology platform, which is expected to overcome resistance challenges of existing TOPO1 payloads, such as target mutations and BCRP-mediated efflux, and provide a novel payload option for the development of next-generation XDC drugs (ADCs, SMDCs, and PDCs). Genuine Biotech looks forward to working with industry partners to jointly advance the clinical translation of this innovative platform and benefit more cancer patients worldwide.