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.
Highlights
Apoptosis, Immunity and Cancer Group, Aragón Health Research Institute (IIS-Aragón), Department of Biochemistry and Molecular Biology, Faculty of Chemical Sciences, Complutense University, 28040 Madrid, Spain
The bacterial toxins Pseudomonas Exotoxin A (PE) and Diphtheria toxin (DT) together with the plant ribosome-inactivating proteins (RIP) ricin and aspirin have been most frequently studied for therapeutic purposes but several others are under evaluation, predominantly in the oncological field [10,11,12,13]
Αsarcin stands out as the most representative member. Their cytotoxic character is due to their ability to interact with acidic phospholipids, which are abundant in the tumor cell membranes, allowing them to internalize to the cytosol where they exert their ribonucleolytic activity. Ribotoxins exert their specific activity on the same target as RIP, the sarcin–ricin loop (SRL), causing a single cleavage of rRNA that leads to ribosome inactivation and protein biosynthesis inhibition, resulting in cell death by apoptosis
Summary
ITX combine the cell-killing ability of a toxin with the specificity of a monoclonal antibody (mAb), overcoming the limitations of each [15]. Hundreds of third-generation ITX have been developed, and several PE-based ITX demonstrated promising activity in clinical and pre-clinical studies conducted by the Ira Pastan group Both moxetumomab pasudotox and oportuzumab monatox belong to this category of recombinant ITX. Several human proteins have been used to generate these fourth-generation ITX, including the microtubule-associated protein tau, RNases, granzyme B, death-associated protein kinase [26] and, more recently, granulysin [27,28] Among those approaches, granzyme B-based ITX have been the most studied and further improved, demonstrating a therapeutic effect in several preclinical models in vivo [24]. ABD: albumin-binding domain; bs: bispecific; bp: biparatopic; CEA: carcinoembryonic antigen; DT390: truncated version of diphtheria toxin (DT) comprising the first 389 aminoacids; EGFR: epidermal growth factor receptor; EpCAM: epithelial cell adhesion molecule; Fab: antigen-binding fragment; LY : Lewis Y antigen; PE: Pseudomonas exotoxin A; PE38: truncated PE (38kDa); PE24: truncated PE (24 kDa); scFv: single-chain Fv; sdAb: single-domain antibody; TIE: collagen trimerization domain; Tn: tumor-associated carbohydrate antigen (α-O-GalNAc-Ser/Thr)
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