Effective antitumor therapy based on a novel antibody-drug conjugate targeting the Tn carbohydrate antigen.
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.
Institut Curie, PSL Research University, Paris, France; INSERM U932, Paris, France; Centre d'Investigation Clinique Biothérapie CICBT 1428, Institut Curie, Paris, France.
Christine
C
Sedlik
Institut Curie, PSL Research University, Paris, France; INSERM U932, Paris, France; Centre d'Investigation Clinique Biothérapie CICBT 1428, Institut Curie, Paris, France.
Adèle
A
Heitzmann
Institut Curie, PSL Research University, Paris, France; INSERM U932, Paris, France.
Sophie
S
Viel
Institut Curie, PSL Research University, Paris, France; CNRS UMR3666/INSERM U 1143, Paris, France.
Rafik
R
Ait Sarkouh
Institut Curie, PSL Research University, Paris, France; CNRS UMR3666/INSERM U 1143, Paris, France.
Cornélie
C
Batisse
Institut Curie, PSL Research University, Paris, France; CNRS UMR3666/INSERM U 1143, Paris, France.
Frédéric
F
Schmidt
Institut Curie, PSL Research University, Paris, France; INSERM U932, Paris, France.
Philippe
P
De La Rochere
Institut Curie, PSL Research University, Paris, France; INSERM U932, Paris, France; Centre d'Investigation Clinique Biothérapie CICBT 1428, Institut Curie, Paris, France.
Nathalie
N
Amzallag
Departamento de Inmunobiología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay; Institut Pasteur de Montevideo, Montevideo, Uruguay.
Eduardo
E
Osinaga
Departamento de Inmunobiología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay; Institut Pasteur de Montevideo, Montevideo, Uruguay.
Pablo
P
Oppezzo
Departamento de Inmunobiología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay; Institut Pasteur de Montevideo, Montevideo, Uruguay.
Otto
O
Pritsch
Département de Biologie des Tumeurs, Institut Curie , Paris, France.
Xavier
X
Sastre-Garau
Institut Curie, PSL Research University, Paris, France; INSERM U932, Paris, France; Centre d'Investigation Clinique Biothérapie CICBT 1428, Institut Curie, Paris, France.
Pascale
P
Hubert
Institut Curie, PSL Research University, Paris, France; INSERM U932, Paris, France; Centre d'Investigation Clinique Biothérapie CICBT 1428, Institut Curie, Paris, France.
Sebastian
S
Amigorena
Institut Curie, PSL Research University, Paris, France; INSERM U932, Paris, France; Centre d'Investigation Clinique Biothérapie CICBT 1428, Institut Curie, Paris, France.
Eliane
E
Piaggio
Biodistribution; MMAF; Tn antigen; internalization; monoclonal antibody-drug conjugate