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.

Novel anti-Sialyl-Tn monoclonal antibodies and antibody-drug conjugates demonstrate tumor specificity and anti-tumor activity

“…The anti-Tn-ADC, called Chi-Tn, is a chimeric antibody generated from an original murine IgM (83D4 50 ) that uses the MMAF payload, relying on cancer cell internalization for efficacy. While Chi-Tn demonstrated efficacy in vitro cytotoxic and in vivo xenograft models, its efficacy was only observed in high Tn-expressing models 48 . Chi-Tn did not demonstrate efficacy in these models when using cells with lower, more heterogeneous Tn expression, perhaps due to the absence of bystander killing with MMAF.…”

“…Tn is normally a building block for other complex sugars, and its expression is generally absent in normal adult tissues. Tn is expressed on cancer cell surfaces in a similar heterogeneous manner to STn when glycosylation is altered, particularly in metastatic lesions 48 . The anti-Tn-ADC, called Chi-Tn, is a chimeric antibody generated from an original murine IgM (83D4 50 ) that uses the MMAF payload, relying on cancer cell internalization for efficacy.…”

Multiple Roles of Glycans in Hematological Malignancies

“…Expression of Cosmc cDNA in Jurkat cells restored C1β3Gal-T activity and T antigen expression ( 49 ). Antitumor drugs with T or Tn antigen as therapeutic target have been developed ( 50 , 51 ).…”

Tumor-associated carbohydrates and immunomodulatory lectins as targets for cancer immunotherapy

“…80 Although initial results were encouraging, the mAb was later discontinued, likely due to low efficacy. More recent attempts at exploiting tumor glycan expression for drug delivery include work by Sedlik et al, who used a Tn-directed mAb (Chi-Tn) to deliver cytotoxic drugs; they showed promising antitumor activity of the chiTn ADC in vitro and in vitro, when this was conjugated to saporin or auristatin F. 81 These effects were particularly dependent on high Tn expression in tumor cells. 81 Similarly, Prendergast et al developed murine mAbs able to target tumor cells expressing STn with high avidity and further exploited a subset of these mAbs as ADCs by conjugating them to monomethyl auristatin E (MMAE).…”

“…More recent attempts at exploiting tumor glycan expression for drug delivery include work by Sedlik et al, who used a Tn-directed mAb (Chi-Tn) to deliver cytotoxic drugs; they showed promising antitumor activity of the chiTn ADC in vitro and in vitro, when this was conjugated to saporin or auristatin F. 81 These effects were particularly dependent on high Tn expression in tumor cells. 81 Similarly, Prendergast et al developed murine mAbs able to target tumor cells expressing STn with high avidity and further exploited a subset of these mAbs as ADCs by conjugating them to monomethyl auristatin E (MMAE). 82 These ADCs showed high efficacy in vitro, in the presence of STn-expressing cancer cell lines, as well as tumor inhibition in multiple in vivo model, including breast and colorectal cancer.…”