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2018 2018

(2) 撰稿者：陳鈴津特聘講座教授暨副所長

Alice L. Yu, M.D., Ph.D.

GD2-targeted Cancer Immunotherapy

1.Clinical development of anti-GD2 Mab:

Until recently, all approved cancer immunotherapeutics target proteins but not
glycans. The approval of Unituxin, a chimeric anti-GD2 antibody, ch14.18 for the

treatment of high-risk neuroblastoma by US FDA and European Commission in
2015 marks the first new agent targeting a glycolipid molecule, thereby widening

the net of potential pharmaceutical targets. This was largely based on the pioneer

work of Dr. Yu and her leadership through the entire course of ch14.18 development
culminating in a randomized phase III clinical trial, led by Dr. Yu, under the auspice

of Children’s Oncology Group. This trial showed a significant improvement in
2-year event-free survival and overall survival (New Engl J Med, 2010) and provided

As shown, ten biotinylated lysine residues, including K185, K268, K340, K521, K522, the basis for its regulatory approval. This immunotherapy has since become the
K523, K581, K585, K620 and K621 were found in the MS/MS spectra of the GRP78 new standard of care for neuroblastoma. To improve the efficacy of Unituxin,

extracellular domain profiling. Interestingly, these biotinylated lysine residues were Dr. Yu proposed a COG study to combine chemotherapy with Unituxin in relapsed

mainly identified on the peptide- binding domain,including both the βsandwich neuroblastoma. The impressive clinical response (5/17 response vs. 1/17 without
subdomain and helix-bundle subdomain. We also observed variation in the frequencies Unituxin) was showcased at ASCO 2016 and published in Lancet Oncology 2017.

of biotinylation for a particular lysine residue, presumably due to the steric hindrance This study has since been expanded to accrue 50 more patients to aim for
effects. A summary of the identified biotinylation sites and the frequency of 2nd indication of Unituxin. We are now developing a clinical trial of

identified biotinylation are given in figure below. In total, the identification of these combining Unituxin with chemotherapy for newly

nine biotinylated lysine residues confirmed that peptide-binding domain of GRP78 is diagnosed high risk neuroblastoma.
exposed extracellularly.

Reference:

1.Wang S.H., Lee A.C., Chen I.J., Chang N.C., Wu H.C., Yu H.M., Chang Y.J.,

Lee T.W., Yu J.C., Yu A.L.*, Yu J.* Structure-based optimization of GRP78-
binding peptides that enhances efficacy in cancer imaging and therapy.

Biomaterials 2016, 94:31-44.

2.Wang S.H., Yu J.* Data for peptide-binding assay with oriented
immobilization of GRP78 in Biacore. Data in Brief 2016, 7:1696-1699.

3.Wang S.H., Yu J.* Structure-based design for binding peptides in anti-cancer
therapy. Biomaterials 2018, 156: 1-15.

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