In vivo surveillance and elimination of teratoma‐forming human embryonic stem cells with monoclonal antibody 2448 targeting annexin A2

Abstract

This study describes the use of a previously reported chimerised monoclonal antibody (mAb), ch2448, to kill human embryonic stem cells (hESCs) in vivo and prevent or delay the formation of teratomas. ch2448 was raised against hESCs and was previously shown to effectively kill ovarian and breast cancer cells in vitro and in vivo. The antigen target was subsequently found to be Annexin A2, an oncofetal antigen expressed on both embryonic cells and cancer cells. Against cancer cells, ch2448 binds and kills via antibody‐dependent cell‐mediated cytotoxicity (ADCC) and/or antibody‐drug conjugate (ADC) routes. Here, we investigate if the use of ch2448 can be extended to hESC. ch2448 was found to bind specifically to undifferentiated hESC but not differentiated progenitors. Similar to previous study using cancer cells, ch2448 kills hESC in vivo either indirectly by eliciting ADCC or directly as an ADC. The treatment with ch2448 post‐transplantation eliminated the in vivo circulating undifferentiated cells and prevented or delayed the formation of teratomas. This surveillance role of ch2448 adds an additional layer of safeguard to enhance the safety and efficacious use of pluripotent stem cell‐derived products in regenerative medicine. Thereby, translating the use of ch2448 in the treatment of cancers to a proof of concept study in hESC (or pluripotent stem cell [PSC]), we show that mAbs can also be used to eliminate teratoma forming cells in vivo during PSC‐derived cell therapies. We propose to use this strategy to complement existing methods to eliminate teratoma‐forming cells in vitro. Residual undifferentiated cells may escape in vitro removal methods and be introduced into patients together with the differentiated cells.

Annexin Animal Models—From Fundamental Principles to Translational Research

“…AnxA2 antibody-conjugated and curcumin-loaded nanoparticles effectively accumulated in tumours, providing sustained release of curcumin with potential to reduce metastatic breast cancer progression [ 163 ]. A monoclonal AnxA2 antibody not only allowed monitoring EMT in breast and ovarian cancers, but also provided antibody-dependent cell toxicity and efficient killing when conjugated to cytotoxic drugs and expressed as a chimeric immunoglobulin G1 [ 164 , 165 , 166 ]. Other beneficial effects of AnxA2 antibodies include the inhibition of neoangiogenesis in TNBC xenograft models, which involves reduced plasmin generation as well as loss of AnxA2 tyrosine 23 phosphorylation [ 167 , 168 ].…”

Advances in cancer treatment: a new therapeutic target, Annexin A2

“…Simeon Cua and his colleagues generate a mAb, IgG1 2448, targeting a unique glycan epitope on ANXA2. It demonstrated good anti-tumor efficacy in vivo and indicated that 2448 can be a potential candidate of targeted therapy for ovarian and breast cancer [132,133].…”

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

“…Recently, our group proposed a strategy to complement existing methods that eliminate teratoma-forming cells in vitro [50]. Residual undifferentiated PSCs could possibly escape in vitro removal methods and be introduced into patients together with the differentiated cells.…”

“…Another hESC mAb, 2448, binds to annexin A2 on hESCs and on cancer cells [34,50]. Cua et al showed that the mAb binds to glycans on annexin A2, which confers the mAb a unique property.…”