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Gastrointestinal tumors (GIC, includinggastric cancer , pancreatic cancer ,colorectal cancer ) and neuroendocrine tumors (NETs) are often fatal after metastasis
Pancreatic cancerColorectal cancer molecular targets immune leukemia lymphoma
To date, FDA - approved CAR-T therapies have targeted tumor-associated antigens (TAAs), such as CD19, which are also expressed in certain normal cells, resulting in the elimination of normally antibody-producing B cells, requiring injections of human IgG to rescue
FDA CAR-T source:Nature Cancer
On March 21, researchers at the Perelman School of Medicine at the University of Pennsylvania published their latest study in Nature Cancer, including Carl June
First, to overcome the limitations of the lack of valuable TAAs and cognate monoclonal antibodies, we developed an unbiased phage display screening method to identify camelid-derived single domains that preferentially bind to the cell surface of GI-NETs Antibodies (nanobodies, VHH) and isolated VHH1 that specifically binds to NETs
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Based on the findings of the first step, the researchers developed a CDH17-targeting nanobody VHH1-driven CAR-T (CDH17CART)
Source: Nature Cancer
Source: Nature CancerNotably, CDH17 CART does not attack normal intestinal epithelial cells that also express CDH17 to cause toxicity
Further studies revealed that CDH17 was only localized and restricted to the lateral membranes of tight junctions between intestinal epithelial cells, and was not expressed on the apical or basal surfaces (k, n below)
CDH17CART significantly infiltrated NETNT-3 tumors but avoided Cdh17-expressing healthy mouse tissue
At present, Boehringer Ingelheim’s TRAILR2/CDH17 bispecific antibody BI 905711 has the fastest progress in research on CDH17 targets, which is in Phase I/II clinical stage
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