Recently, the CBI 2026 Biomedical Innovation Expo concluded in Suzhou, with an exhibition area of over 36,000 square meters and more than 20,000 participants gathered on site to jointly create a new industry ecosystem. The conference featured multiple parallel forums. At the ADC New Drug Discovery and Front-End Technology Innovation Forum, Dr. Dang Qun, President of Real Biotechnology, shared the company's latest achievements in overcoming ADC drug resistance with its novel non-camptothecin TOPO1 inhibitor platform.

Image

Precision therapeutic approaches represented by next-generation ADC drugs are reshaping the landscape of tumor treatment, among which TOPO1 inhibitor payloads are the most widely used clinically. However, with the widespread use of such drugs, issues of TOPO1 toxin-related target mutations and efflux pump resistance have become increasingly prominent, with cross-resistance emerging among different antibody ADCs, becoming a key bottleneck constraining efficacy improvement.

Since the discovery of camptothecin in 1966, the core scaffold of camptothecin-class TOPO1 inhibitors has remained unchanged for over 60 years. Faced with the drug resistance dilemma of existing toxins, can the discovery of a new generation of TOPO1 inhibitors crack this problem? Real Biotechnology has conducted in-depth research on this.

Through its independently developed AI-computer-aided drug design (CADD) method, Real Biotechnology successfully replaced one of the five rings in the camptothecin core scaffold, thereby discovering a new generation of innovative TOPO1 inhibitors and a novel ADC payload platform.

At the outset of design, the R&D team fully considered the structural characteristics of the camptothecin core. AIDD modeling studies showed that the R364H mutation shortens residue 364, leading to the loss of a key hydrogen bond with the nitrogen atom of the camptothecin core B ring. This problem also exists in current camptothecin-class TOPO1 inhibitors.

To effectively act on the mutated R364H residue, the team replaced the B-ring nitrogen atom with a longer hydrogen bond acceptor—a ketone group—and redesigned the core scaffold. AIDD molecular modeling showed that the novel TOPO1 inhibitor can maintain strong hydrogen bond interactions with both wild-type and mutant R364H residues of TOPO1.

In addition, BCRP-mediated drug efflux often leads to resistance to many chemotherapeutic drugs. To address this issue, the team used AIDD models to conduct lead compound optimization to guide compound selection. Modeling results showed that by introducing a rotation-restricted conformation, the transition of the BCRP nucleotide-binding domain from an open conformation to a closed conformation can be prevented, thereby improving the compound's BCRP substrate activity and fundamentally avoiding active clearance of the drug by efflux pumps.

ZSSW-136 is the first small-molecule PCC compound discovered on this platform, with unique advantages in overcoming common anti-tumor drug resistance. Preclinical studies showed that ZSSW-136 has broad-spectrum anti-tumor activity in cell experiments and is not a BCRP substrate. In primary drug-resistant organoid models, its inhibitory effect on irinotecan-resistant human cancer organoids was 400 times that of irinotecan; in secondary drug-resistant organoid models, ZSSW-136's anti-tumor activity was 50-180 times higher than that of irinotecan. Preclinical in vivo PDX model test results showed that in irinotecan-resistant colorectal cancer and etoposide-resistant small cell lung cancer models, ZSSW-136 significantly inhibited tumor growth at doses of 0.5 and 1 mpk.

In terms of safety, ZSSW-136 also performed excellently. In the CD34+ hematopoietic stem cell toxicity assessment in preclinical trials, its safety was 3.2 times that of the existing camptothecin-class toxin DXD, demonstrating a larger safety window.

Currently, the company has built a global intellectual property layout around this non-camptothecin TOPO1 inhibitor technology platform. This platform is expected to break through the drug resistance problems of existing TOPO1 toxins in target mutations, BCRP efflux, and other aspects, providing a new payload option for the development of next-generation XDC drugs (ADC, SMDC, PDC). Real Biotechnology looks forward to joining hands with industry partners to jointly advance the clinical translation of this innovative platform and benefit more tumor patients worldwide.

Efung Capital participated in multiple rounds of investment in Real Biotechnology from 2021 to 2022. Looking ahead, Yifeng Capital will continue to accompany Real Biotechnology, helping it achieve continuous breakthroughs in the field of innovative drug R&D and bring more treatment options to tumor patients worldwide.

END

[Disclaimer]

The content of this article represents only the views of the Company based on current public information and materials provided by portfolio companies, and does not constitute any investment advice, medical advice, or guarantee of specific company performance. Investment involves risks; market entry should be cautious. Readers should make independent judgments based on public information. Unauthorized reproduction or use for commercial purposes is prohibited.