Effective antitumor therapy based on a novel antibody-drug conjugate targeting the Tn carbohydrate antigen

ABSTRACT

Antibody-drug conjugates (ADC), combining the specificity of tumor recognition by monoclonal antibodies (mAb) and the powerful cytotoxicity of anticancer drugs, are currently under growing interest and development. Here, we studied the potential of Chi-Tn, a mAb directed to a glyco-peptidic tumor-associated antigen, to be used as an ADC for cancer treatment. First, we demonstrated that Chi-Tn specifically targeted tumor cells in vivo. Also, using flow cytometry and deconvolution microscopy, we showed that the Chi-Tn mAb is rapidly internalized – condition necessary to ensure the delivery of conjugated cytotoxic drugs in an active form, and targeted to early and recycling endosomes. When conjugated to saporin (SAP) or to auristatin F, the Chi-Tn ADC exhibited effective cytotoxicity to Tn-positive tumor cells in vitro, which correlated with the level of tumoral Tn expression. Furthermore, the Chi-Tn mAb conjugated to auristatin F also exhibited efficient antitumor activity in vivo, validating for the first time the use of an anti-Tn antibody as an effective ADC.

KEYWORDS:

• Biodistribution
• internalization
• MMAF
• monoclonal antibody-drug conjugate
• Tn antigen

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Acknowledgments

We thank the Cytometry Platform, the Nikon Imaging Center, and the Animal facilities of the Institut Curie. We acknowledge the CIC IGR-Curie 1428 (Center Of Clinical Investigation), Institut Curie, Paris; the ECOS-Sud program, Université de Paris, ANR-2010-EMMA-015-01, Medicen Paris Region, SiRIC (Grant INCa-DGOS-4654), ANR-10-IDEX-0001-02 PSL*, and ANR-11-LABX-0043. We also specifically thank André Nicolas from the Platform of Experimental Pathology of the Institut Curie and Virginie Premel for their help in IHC.

Funding

This work was supported by fundings from the Institut National de la Santé et de la Recherche Médicale (INSERM); the Association pour la Recherche sur le Cancer (ARC); the Institut Curie; the Agence Nationale pour la Recherche (ANR Emergence program), and the Institut National du Cancer (INCa).