GlyCLICK®-generated ADC Suppresses Tumor Growth in Pancreatic Cancer Models
Scientists at The Finsen Laboratory and collaborators have described the potential for a novel antibody-drug conjugate (ADC) to treat pancreatic ductal adenocarcinoma (PDAC). The ADC candidate is conjugated with a highly potent anthracycline payload (PNU-159682) using GlyCLICK conjugation technology, and targets uPAR (urokinase plasminogen activator receptor), a protein overexpressed in PDAC and its surrounding stroma. GlyCLICK facilitated the site-specific attachment of the payload to the antibody’s Fc-glycans, ensuring a precise drug-to-antibody ratio (DAR) of 2. This study highlights how GlyCLICK’s precision and efficiency significantly enhanced the development, efficacy, and safety of the ADC molecule.
PDAC is among the deadliest cancers, with a 5-year survival rate below 10%, owing to its dense, desmoplastic stroma that impedes drug delivery and creates an immunosuppressive tumor microenvironment. ADCs that deliver a targeted cytotoxic payload have shown robust proof-of-concept in various solid tumors. Compared to functional antagonist approaches, ADCs can elicit orthogonal killing mechanisms, like bystander cell cytotoxicity or immunogenic cell death with the potential to amplify the overall antitumor response by alleviating constraints of target heterogeneity and immunosuppression.
Here, the scientists aimed to address the challenges of treating PDAC using uPAR as a therapeutic target for delivering cytotoxic drugs. The primary objectives were to evaluate uPAR as an effective target for ADC treatment and demonstrate preclinical efficacy of the GlyCLICK-generated putative ADC candidate. This will provide preclinical evidence supporting the potential of a therapeutic candidate for PDAC, with the long-term goal of advancing it as a standalone treatment or in combination with other immunotherapies. By achieving these goals, the study sought to establish a new targeted therapeutic approach for PDAC, leveraging GlyCLICK as a site-specific ADC-generating technology to overcome the limitations of conventional therapies.
Figure 1. GlyCLICK is a three-step conjugation technology for site-specific and quantitative conjugation of IgG from several species and subclasses.
Potent, uPAR-dependent cytotoxicity across multiple PDAC cell lines was demonstrated in vitro, and the ADC candidate also demonstrated bystander effects, killing uPAR-negative cells through the release of the cytotoxic payload from neighboring uPAR-positive cells. Tumor growth in both xenograft and syngeneic PDAC models was significantly reduced in vivo through the promotion of immune cell infiltration while reducing suppressive myeloid cells. Using GlyCLICK technology to generate the site-specific ADC candidate ensured reproducibility, optimized the therapeutic window, and minimized off-target toxicity by reducing Fc-mediated interactions. The controlled conjugation process enhanced ADC stability and pharmacokinetics, preventing premature drug release and ensuring efficient delivery to uPAR-positive cells. Additionally, GlyCLICK’s compatibility with the lysosomally cleavable valine-citrulline linker allowed for selective payload release within target cells, maximizing cytotoxicity while sparing healthy tissues which, collectively improved the safety, efficacy, and clinical potential of the ADC candidate.
This study highlights uPAR as a viable therapeutic target for PDAC and underscores the potential of GlyCLICK-generated site-specific ADCs to overcome the challenges of treating stroma-rich, therapy-resistant cancers. The findings pave the way for future clinical translation and precision medicine approaches in uPAR-positive cancers. The putative ADC candidate represents a promising potential therapeutic treatment option for PDAC and provides a foundation for potential clinical implementation and future GlyCLICK-enabled ADC innovations.
Reference
Metrangolo et al., 2025. Targeting uPAR with an antibody- drug conjugate suppresses tumor growth and reshapes the immune landscape in pancreatic cancer models. Sci. Adv.
GlyCLICK® Azide Activation – Site-specific conjugation of IgG with azide-alkyne click chemistry