Background Autologous or allogeneic natural killer (NK) cells possess efficient cytotoxicity against tumor cells without severe side effects such as CRS or graft-versus-host disease (GvHD). In addition to chimeric antigen receptor (CAR) strategy, antibody-cell conjugates (ACC) platform provides more efficient way to arm NK cells with binding specificity and enhanced potency against target cells. In this work, we develop a NK cell therapy product ACE1702, a novel NK cell line oNK conjugated with trastuzumab, and assess its potency against HER2+ solid tumors.
Methods oNK cells were covalently conjugated with monoclonal antibody Trastuzumab after sublethal irradiation by our patented antibody-cell conjugates (ACC) platform to become our cryopreserved final product ACE1702 compliant with current good manufacturing practice (cGMP). Function of ACE1702 was validated by real-time xCELLigence analyzer and MTT assay in vitro. Efficacy of intraperitoneally (ip.) delivered ACE1702 was evaluated in tumor-bearing female immune compromised NSG mice. Characterization of ACE1702 was analyzed by flow cytometry.
Results We demonstrated that the trastuzumab-armed oNK cells, ACE1702, exerted human epidermal growth factor 2 (HER2) binding specificity and enhanced cytotoxicity against various types of cancer cells with different grade of HER2 expressions compared to control oNK cells in vitro. In vivo results in human ovarian cancer cell line SK-OV-3-bearing xenograft mouse model further supported the in vitro observations. Of note, ACE1702 also displayed a better cytotoxicity against HER2+ cancer cells than trastuzumab and its derived antibody-drug conjugate. ACE1702 also remained cytotoxicity against cancer cells in the suppressive tumor microenvironment. Characterization revealed a preferential expression of NK activation receptors, and conjugation of trastuzumab with cell membrane proteins responsible for NK activity capacitated ACE1702 with enhanced cytotoxicity. These results underscore the potency of ACE1702 in eradication of cancer cells.
Conclusions Here we introduced a novel trastuzumab-modified oNK cell product with enhanced specificity against myriad types of HER2+ cancers. Selective conjugation of trastuzumab with membrane proteins contributing to NK activation conferred ACE1702 with enhanced cytotoxicity even in the suppressive tumor microenvironment.
Trial Registration None
Ethics Approval The animal study was conducted according to protocols approved by the Institutional Animal Care and Use Committee of Muragenics.
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