Abstract 100P
Background
Currently, not only TROP2, EGFR, and VEGF—which are already approved—but also MUC1, Mesothelin, CEACAM6, GPNMB, CXCR4, and Claudin18.2 have been proposed as drug targets for HER2-negative breast cancers. These molecules are significantly overexpressed in cancer cells, enabling differentiation from normal cells and making them attractive candidates for drug development strategies such as antibody-drug conjugates (ADCs), T cell bispecific engagers (TCBs), and CAR-T therapies. If more specific target molecules could be identified, even more effective therapeutics might be developed. COGNANO, Inc. and collaborators aimed to discover novel target specific for unmet cancers.
Methods
We conducted long-term immunization of alpacas, which produce single-domain antibodies, using more than 10 types of human TNBC cell lines. Over time, we constructed a large library of VHH antibodies that recognize cell surface proteins. Leveraging this library, we developed an algorithm to cluster millions of antibody amino acid sequences in silico and identify characteristic clusters unique to each TNBC cell line. The Inverse Biomarker Exploring Technology (IBMET) is a bio-AI fusion platform that converts biologically generated single-domain antibodies into a digital library, enabling the discovery of novel biomarker molecules by using epitope-correlated features as indicators.
We validated antibodies recognizing novel markers in patient tissues and identified several biomarkers, including the most distinctive: VHH89T antigen.
Results
We formulated VHH89T into an ADC conjugated with the payload SN-38 and tested its cytotoxic activity in cultured cells, achieving highly favorable results. Additionally, its efficacy was confirmed in a mouse xenograft model.
Conclusions
The novelty and advantages of IBMET® include: Based on structural abnormalities, immediate drug formulation upon novel target discovery, as antibodies are already available. Parallel development of companion diagnostics, enabling rapid and comprehensive drug development. Here we propose a new Tech-Bio methodology suitable for immuno-oncotherapy.
Clinical trial identification
Editorial acknowledgement
Kyoto Industrial Support Organization 21
The Ministry of Economy, Trade and Industry (METI)
The Japan External Trade Organization(JETRO)
Kyoto Prefecture
Kyoto City
Legal entity responsible for the study
The KYODOKEN Institutional Animal Care and Use Committee approved the protocols for these studies (approval number 20200312).
Funding
Kyoto Industrial Support Organization 21 The Ministry of Economy, Trade and Industry (METI), The Japan External Trade Organization (JETRO), Kyoto Prefecture Kyoto City.
Disclosure
All authors have declared no conflicts of interest.