Opportunities for Antibody Discovery Using Human Pluripotent Stem Cells: Conservation of Oncofetal Targets

Abstract

Pluripotent stem cells (PSCs) comprise both embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). The application of pluripotent stem cells is divided into four main areas, namely: (i) regenerative therapy, (ii) the study and understanding of developmental biology, (iii) drug screening and toxicology and (iv) disease modeling. In this review, we describe a new opportunity for PSCs, the discovery of new biomarkers and generating antibodies against these biomarkers. PSCs are good sources of immunogen for raising monoclonal antibodies (mAbs) because of the conservation of oncofetal antigens between PSCs and cancer cells. Hence mAbs generated using PSCs can potentially be applied in two different fields. First, these mAbs can be used in regenerative cell therapy to characterize the PSCs. In addition, the mAbs can be used to separate or eliminate contaminating or residual undifferentiated PSCs from the differentiated cell product. This step is critical as undifferentiated PSCs can form teratomas in vivo. The mAbs generated against PSCs can also be used in the field of oncology. Here, novel targets can be identified and the mAbs developed as targeted therapy to kill the cancer cells. Conversely, as new and novel oncofetal biomarkers are discovered on PSCs, cancer mAbs that are already approved by the FDA can be repurposed for regenerative medicine, thus expediting the route to the clinics.

Targeting tumor lineage plasticity in hepatocellular carcinoma using an anti-CLDN6 antibody-drug conjugate

“…Tumor cells hijack developmental signaling to gain lineage plas ticity and evolve toward drugrefractory identities. Oncofetal proteins, which are encoded by highly expressed genes during em bryonic development that are silenced in terminally differentiated cells, provide ideal targets for immunebased drug development, because these proteins are not present in normal healthy adult tis sue, reemerge in tumor cells, and tend to be immunogenic (20). Previously, we showed that human embryonic stem cells (hESCs) differentiated into mature hepatocytes along hepatic lineages using transcriptomic RNA sequencing (RNAseq) to profile the genes actively expressed during liver development but silenced in the mature hepatocytes (21).…”

Editorial for the Special Issue “New Strategies in Cancer Pharmacotherapy: Development of Hormonal Antineoplastic Drugs, Cytotoxic Drugs and Targeted Therapies”

“…The review by Tan and Choo explores the application of pluripotent stem cells (PSCs) for the discovery of new biomarkers and generating antibodies against those biomarkers. The monoclonal antibodies generated against PSCs might have applications in cancer-targeted therapy to kill cancer cells, and conversely, monoclonal antibodies already in use in cancer might be repurposed for regenerative medicine, making it safer [11]. Grywalska et al review the use of currently available immune checkpoint inhibitors in cervical, endometrial, and ovarian cancers.…”