A Novel Therapeutic Strategy for Pancreatic Cancer: Targeting Cell Surface Glycan Using rBC2LC-N Lectin–Drug Conjugate (LDC)
The clinical applications of antibody drugs targeting cancer cells are highly limited as they mainly function on
peptides or cell transmembrane proteins. The glycomes of cancer cell surface are often unique with aberrant
glycosylation, which makes them a more effective strategy for cancer targeting. Lectins are potential to be the
alternative to antibodies as they can recognize glycans.
Osamu Shimomura et al. researched whether lectin–drug conjugate (LDC) that uses lectin as a drug carrier could be
used for in vivo PDAC cancer therapy.
Materials & Methodologies
The materials and methods adopted in this research are as follows.
Six human pancreatic cancer cell lines with various cell differentiation states in their origin.
69 resected pancreatic adenocarcinoma specimens were used, with 7 poorly differentiated (P/D) cases, 53
moderately differentiated (M/D) cases, and 9 well-differentiated cases.
High-density lectin microarray was prepared from 0.5 mg/mL Cy3-labelled lysate.
Generate rBC2-PE38 (371 amino acids) by structure reconstruction of recombinant N-terminal domain of BC2L-C,
which was then expressed in E. coli and purified by one-step affinity chromatography on an
Assays were used for comprehensive assessments, which are lectin binding analysis by MFI and GraphPad Prism 6,
and cell viability assessment via MTT assay.
Blood samples of four types from four healthy volunteers were used after centrifugation to observe
Conduct toxicology study of LDC in wild-type mice.
PDAC models: subcutaneous cell xenograft model, subcutaneous PDX model, pancreatic orthotopic model, and
peritoneal dissemination model
The study obtained phased results in the following aspects.
Capan-1 cells are the most suitable PDAC cell lines that maintain well-to-moderately differentiated tumor
features and thus represent the dominant morphology of clinical PDAC characteristics.
A TNF-like lectin, rBC2LC-N (recombinant N-terminal domain of BC2L-C) lectin that specifically binds to
fucosylated glycan epitopes of H type 1/3/4 trisaccharides exhibited specific affinity for Capan-1 cells and
clinical PDAC samples.
Meanwhile, the team studied whether using selected lectin as a drug carrier would be safe during administration
by in vitro and in vivo tests. The results showed that rBC2LC-N reactivity is unlikely to cause hemagglutination
in human blood. In addition, in both i.p. and i.v. injections to mice models, administration of BC2LC-N lectin
without conjugated toxin did not cause death at any dose tested up to 15 mg/mouse (892.5 mg/kg).
LDC revealed certain therapeutic effects in various tumor models, including subcutaneous xenografts treated by
local injection, subcutaneous PDX xenografts treated by i.p. or i.v. injection, pancreatic orthotopic xenografts
treated by i.p. or i.v. injection, and peritoneal dissemination models treated by i.p. or i.v. injection.
In this study, Osamu Shimomura's team discovered that rBC2LC-N is the most highly reactive lectin in PDAC and the
specific affinity between the rBC2LC-N lectin and the PDAC cell surface glycans. Meanwhile, the safety of rBC2LC-N
lectin as drug carrier was preliminarily verified. Furthermore, the LCD showed therapeutic effects in several mouse
models. Even though the affinity between lectin to the targeting glycan is weaker than that of antibody to antigen,
with the help of current technologies, it is hopeful that novel lectins can be used as drug carriers. The study
provides new insights into cancer treatments that might serve as alternatives to expensive antibody-based drugs.
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