How glycan targeted drug discovery for cancer should be

How glycan targeted drug discovery for cancer should be

Glycans, as is said to be the face of cells, greatly change the structure depending on the state of the cell. It is known that specific changes in the glycan structure occur in canceration, and various diagnostic and therapeutic drugs are under development using glycans as the drug discovery targets. Changes in glycan structure caused by canceration depend on the type of cancer, but common characteristics include followings:

(1) Increase in multi-branching of N-type sugar chains
(2) Shortening of O-type glycan chains
(3) Increase in terminal-sialic acid modification
https://jitc.bmj.com/content/8/2/e001222.long

However, in addition to these, there seems to be a feature that the amount of glycan modification increases when it becomes cancerous, and the high mannose structure increases, too.
https://pubmed.ncbi.nlm.nih.gov/32143591/

Based on the cited papers above, I will summarize the strategy of glycan targeted drug discovery as follows.

  • Antobody-drug conjugates (ADC): target on cancerous cell surface expressing targeted glycans using glycan binding agents (i.e., lectins etc.). In this case, it might work better to adopt bispecific antibodies to glycans on target cancerous cell surface more precisely  (e.g., bispecific to GD2 ganglioside and MUC1)
  • Siglec inhibitors: Siglec is expressed on most of the immune cells, the immune response is suppressed when the signal is triggered by binding to sialoglycan.
  • Galectin inhibitors: tumor cells highly express galectins, and bind to immune checkpoint CTLA-4 to suppress the immune response. Galectin-1 induces apoptosis of T- cells.
  • Immune checkpoint inhibitors: PD-1/PD-L1 are also strongly glycosylated, and molecular-targeted drugs with those excellent inhibitory effects are promising.
  • C-type lectins: DC-SIGN, Dectin-1 and others promote anti-tumor activity, while NK62DG and Mincle work immuno-suppressively
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