Antibody-Based Immunotoxins for Colorectal Cancer Therapy

Abstract

Monoclonal antibodies (mAbs) are included among the treatment options for advanced colorectal cancer (CRC). However, while these mAbs effectively target cancer cells, they may have limited clinical activity. A strategy to improve their therapeutic potential is arming them with a toxic payload. Immunotoxins (ITX) combining the cell-killing ability of a toxin with the specificity of a mAb constitute a promising strategy for CRC therapy. However, several important challenges in optimizing ITX remain, including suboptimal pharmacokinetics and especially the immunogenicity of the toxin moiety. Nonetheless, ongoing research is working to solve these limitations and expand CRC patients’ therapeutic armory. In this review, we provide a comprehensive overview of targets and toxins employed in the design of ITX for CRC and highlight a wide selection of ITX tested in CRC patients as well as preclinical candidates.

Preclinical Studies of Granulysin-Based Anti-MUC1-Tn Immunotoxins as a New Antitumoral Treatment

“…However, systemic treatment of tumors would require improving the directionality of the molecule. This can be achieved by the conjugation of an antibody or antibody fragment directed against a tumor molecule with GRNLY, generating a so-called fourth-generation immunotoxin [ 16 ]. Our team designed three immunotoxins that conjugated GRNLY with scFv, one directed against CEA (Carcino-embryonic antigen) [ 21 ], and two against the Tn antigen [ 22 ].…”

“…Recently, the immunotoxin moxetumomab pasudotox, an anti-CD22 scFv fused with the Pseudomonas Exotoxin A PE38 has been approved for the treatment of hairy cell leukaemia [ 15 ]. Another PE38-based immunotoxin, oportuzumab monatox, which includes an scFv directed against EpCAM was in review as of August 2021 for bladder cancer treatment [ 16 ]. On the othe hand, our research group has studied the antitumor capacity of recombinant 9 kDa granulysin (GRNLY) for more than two decades [ 17 , 18 , 19 , 20 ].…”

“…Previous studies showed the in vivo tumor targeting of MFE23GRNLY, an immunotoxin engineered against the carcinoembryonic antigen (CEA), after systemic injection [ 21 ]. This therapy would be directed to tumors with high expression of CEA, mostly colorectal or gastric tumors [ 16 ]. Since the expression of the Tn antigen is observed in a much wider variety of tumor types, targeting this antigen would expand the possible therapeutic applications of granulysin-based immunotoxins.…”

Antibody Based Delivery of Toxins and Other Active Molecules for Cancer Therapy

“…Two review articles exploited the possibility of application of immunoconjugates (IC) for the therapy of colorectal cancer [ 14 ] and sarcoma [ 15 ].…”

“…Several monoclonal antibodies (mAbs) are included among the treatment options for advanced CRC, but often they may have limited clinical activity. The review article by Sanz et al [ 14 ], reported data about the wide variety of ICs tested in preclinical studies and clinical trials for CRC treatment. For each conjugate, the target, the carrier and payload are described in detail and the preclinical efficacies in vitro and in vivo are reported.…”