Journal article
Targeting a Tumor-Specific Epitope on Podocalyxin Increases Survival in Human Tumor Preclinical Models
University of British Columbia1
Department of Biotechnology and Biomedicine, Technical University of Denmark2
Section for Protein Science and Biotherapeutics, Department of Biotechnology and Biomedicine, Technical University of Denmark3
Biotherapeutic Glycoengineering and Immunology, Section for Protein Science and Biotherapeutics, Department of Biotechnology and Biomedicine, Technical University of Denmark4
Centre For Drug Research & Development5
Montreal Institute of Cancer6
University of Copenhagen7
DTU Microbes Initiative, Centers, Technical University of Denmark8
Podocalyxin (Podxl) is a CD34-related cell surface sialomucin that is normally highly expressed by adult vascular endothelia and kidney podocytes where it plays a key role in blocking adhesion. Importantly, it is also frequently upregulated on a wide array of human tumors and its expression often correlates with poor prognosis.
We previously showed that, in xenograft studies, Podxl plays a key role in metastatic disease by making tumor initiating cells more mobile and invasive. Recently, we developed a novel antibody, PODO447, which shows exquisite specificity for a tumor-restricted glycoform of Podxl but does not react with Podxl expressed by normal adult tissue.
Here we utilized an array of glycosylation defective cell lines to further define the PODO447 reactive epitope and reveal it as an O-linked core 1 glycan presented in the context of the Podxl peptide backbone. Further, we show that when coupled to monomethyl auristatin E (MMAE) toxic payload, PODO447 functions as a highly specific and effective antibody drug conjugate (ADC) in killing ovarian, pancreatic, glioblastoma and leukemia cell lines in vitro.
Finally, we demonstrate PODO447-ADCs are highly effective in targeting human pancreatic and ovarian tumors in xenografted NSG and Nude mouse models. These data reveal PODO447-ADCs as exquisitely tumor-specific and highly efficacious immunotherapeutic reagents for the targeting of human tumors. Thus, PODO447 exhibits the appropriate characteristics for further development as a targeted clinical immunotherapy.
Language: | English |
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Publisher: | Frontiers Media S.A. |
Year: | 2022 |
Pages: | 856424 |
ISSN: | 2234943x |
Types: | Journal article |
DOI: | 10.3389/fonc.2022.856424 |
ORCIDs: | 0000-0003-1428-5695 , 0000-0002-0915-5055 , Mainero Rocca, Ilaria and Blixt, Ola |