GPA33-Targeted Trimeric Immunotoxin Exhibits Enhanced Antitumor Activity in Human Colorectal Cancer Xenografts

TL;DR

A new trimeric immunotoxin targeting GPA33 shows improved antitumor effects in human colorectal cancer models.

Contribution

A novel trimeric immunotoxin combining GPA33 targeting and α-sarcin toxin is developed for enhanced colorectal cancer therapy.

Findings

IMTXTriA33αS exhibits greater avidity and toxic load compared to conventional immunotoxins.

The trimeric structure significantly improves in vitro and in vivo antitumor efficacy.

The immunotoxin shows promise for overcoming limitations in solid tumor targeting and toxicity.

Abstract

Immunotoxins are chimeric molecules with high potential as therapeutic candidates that combine antibody specificity to recognize and bind tumor-associated antigens and the cytotoxic potency of the enzymatic activity of a toxin, leading to the selective death of target cells. The use of immunotoxins as therapeutic tools remains limited by various issues, such as selecting the appropriate tumor-associated antigen (TAA), penetration difficulties in solid tumors, low renal clearance, and low toxic payload. For this purpose, in this work we have designed a novel trimeric immunotoxin (IMTXTriA33αS) against colorectal cancer, combining the scFv against GPA33 as a targeting domain and the fungal ribotoxin α-sarcin (αS) as the toxic fragment, linked by a trimerization domain (TIEXVIII). Our results demonstrate that IMTXTriA33αS has greater avidity and toxic load, showing a very significant increase in its in vitro and in vivo antitumor efficacy, due to its trimeric structure.

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