Targeting a cancer-specific LYPD3 glycoform for tumor therapy

Glycotope GmbH’s team published a study about discovering antibody GT-002 that may very well be a viable form for tumour therapy. We’re happy that we had a small hand in helping them out to help shape what could potentially be a big breakthrough in cancer treatment.

Taking into consideration that more than 1 billion people worldwide are obese, another 1.3 billion smoke and 2.3 billion are current drinkers, cancer is a disease that requires significant research focus. (WHO 2022; 2022)

One groundbreaking potential cancer treatment avenue is the exploration of altered glycosylation of proteins and lipids in cancer cells.

GT-002 – A Monoclonal Antibody Pioneering Targeted Therapies

Figure 1. GT-002 stained human FFPE squamous cell carcinomas (SCC) at 10 μg/mL. (A) SCC primary tumors in specific organs. (B) PDX tumor sections from head and neck SCC (HNSCC). Scale bars: 50 µm. (The figure is adapted from Neumann et al. 2023)

Glycotope GmbH has developed GT-002, a monoclonal antibody designed to specifically target the epithelial glycoprotein LYPD3 in the presence of tumor-specific TF O-glycosylation.

Figure 2. Immunohistochemical staining of cryo-preserved healthy human tissue sections by GT-002. (A) Tonsil, esophagus and skin sections were stained with GT-002 and Lupartumab (both 10 μg/mL). (B) Esophagus tissue sections with (w/neu) or without (w/o neu) prior neuraminidase treatment were stained with GT-002 and Lupartumab (both 10 μg/mL). Scale bars indicate 50 µm. (The figure is adapted from Neumann et al. 2023)

GT-002 exhibits unique tumor specificity, demonstrated through extensive analysis on various tumor cell lines and tissues. Notably, GT-002 outperforms Lupartumab, a conventional protein-binding anti-LYPD3 antibody, in terms of reduced binding to normal human tissues. This reduced on-target/off-tumor binding is attributed to the unique glycosylation-dependent recognition of the GT-002 epitope, masked by sialic acid in normal cells.

LYPD3 – A Glycosylphosphatidylinositol-Anchored Cell Surface in Cancer

LYPD3, also known as C4.4A, is a glycosylphosphatidylinositol-anchored cell surface glycoprotein associated with metastasis in rats.

It is linked to carcinogenesis in various human cancers including:

Squamous cell carcinoma of the skin
Head and neck
Oesophagus
Colorectal cancer.

Antibody discovery against LYPD3 was performed by Icosagen, using HybriFree technology, a proprietary technology for the development of monoclonal antibodies from different host species.

Isolated antibodies were from rabbits and chickens that were immunized with purified LYPD3-ECD (extracellular domain) from Glycotope´s proprietary transfected GlycoCells expressing the tumor-specific TF glycosylation of interest. In the end, GT-002 emerged as the top candidate due to its exceptional glycosylation-dependent binding properties.

“The collaboration has been nothing but nice with them thanks to their open and friendly communication. They show German precision - their ideas are thought-out and carefully prepared. Finding those potential therapeutic antibodies makes the work in the antibody discovery department exciting,” commented our Head of Antibody Discovery, Gaily Kivi.

“The GT-002 study demonstrates Glycotope´s approach on how targeting combined protein/carbohydrate epitopes (GlycoTargets) can improve the tumor selectivity of antibodies and reduce on-target/off-tumor binding, which is key for highly potent therapeutic approaches like ADCs, CARs, bispecifics or RIT. There are many more proteins that could be addressed in this innovative way and our collaboration with Icosagen is one important tool to further leverage this potential.

The HybriFree team perfectly implemented our ideas and complex toolbox into well designed mAb discovery campaigns leading to several lead clones, which have the potential to widen the portfolio of treatment options to otherwise undruggable, normal tissue-expressed protein antigens. We love Icosagen´s uncomplicated and efficient way of working and the long term collaboration we established in the last years,” said Johanna Gellert, Head of Program Management.

Glycotope GmbH's facility in Berlin, Germany.

We’re thankful for the opportunity to help you make the next step in cancer treatment.

To get more details, read the publication here.

Ethical approval was not required for the studies on humans in accordance with the local legislation and institutional requirements because only commercially available established cell lines were used.

Neumann T., Hartung E., Gellert J., Weiß L., Weiske M., Kast N., Gurka S., Marinoff S., Jäkel A., Danielczyk A., Kehler P.