Preparation of a novel EGFR specific immunotoxin and its efficacy of anti-colorectal cancer in vitro and in vivo

Wu, Shuifa; Deng, Cuimin; Zhang, Caiyun; Xiong, Jiani; Gu, Xiaofan; Wang, Ze; Tu, Jingjing; Xie, Jianping

doi:10.1007/s12094-020-02548-8

Cited by 5 publications

(2 citation statements)

References 54 publications

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“…V HH EGFRαS showed potent inhibition of tumoral growth in A431-cell-xenografted mice, comparable to other immunotoxins whose in vivo antitumor activity has already been characterized [42]. Tumor growth rebound observed once treatment has been completed could be explained by lower tumor retention of the nanoITX, due to its monovalence or to the fast glomerular clearance of V HH EGFRαS, since its molecular weight (35 kDa) is lower than the glomerular filtration threshold [65,66].…”

Section: Discussionmentioning

confidence: 76%

Nanobody-Based EGFR-Targeting Immunotoxins for Colorectal Cancer Treatment

et al. 2023

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Immunotoxins (ITXs) are chimeric molecules that combine the specificity of a targeting domain, usually derived from an antibody, and the cytotoxic potency of a toxin, leading to the selective death of tumor cells. However, several issues must be addressed and optimized in order to use ITXs as therapeutic tools, such as the selection of a suitable tumor-associated antigen (TAA), high tumor penetration and retention, low kidney elimination, or low immunogenicity of foreign proteins. To this end, we produced and characterized several ITX designs, using a nanobody against EGFR (VHH 7D12) as the targeting domain. First, we generated a nanoITX, combining VHH 7D12 and the fungal ribotoxin α-sarcin (αS) as the toxic moiety (VHHEGFRαS). Then, we incorporated a trimerization domain (TIEXVIII) into the construct, obtaining a trimeric nanoITX (TriVHHEGFRαS). Finally, we designed and characterized a bispecific ITX, combining the VHH 7D12 and the scFv against GPA33 as targeting domains, and a deimmunized (DI) variant of α-sarcin (BsITXαSDI). The results confirm the therapeutic potential of α-sarcin-based nanoITXs. The incorporation of nanobodies as target domains improves their therapeutic use due to their lower molecular size and binding features. The enhanced avidity and toxic load in the trimeric nanoITX and the combination of two different target domains in the bispecific nanoITX allow for increased antitumor effectiveness.

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Section: Discussionmentioning

confidence: 76%

Nanobody-Based EGFR-Targeting Immunotoxins for Colorectal Cancer Treatment

et al. 2023

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“…The ITs which target EGFR may be alternatives to anti-EGFR antibodies and can deliver the toxin moiety with diverse mechanisms of action to kill cancer cells and overcome cancer resistance [ 2 , 6 ]. In this context, several anti-EGFR ITs, including transforming growth factor alpha-fused PE40 toxin (TGFα-PE40) [ 7 ], EGF ligand-fused PE40 toxin (EGF-PE40) [ 6 ], anti-EGFR cetuximab-derived scFv-fused PE toxin [ 8 ], cetuximab IgG antibody-fused Cucurmosin toxin (C-CUS245C) [ 9 ], and anti-EGFR scFv antibody-fused diphtheria toxin (hDT806) [ 10 ], have been generated, but none of them have been approved for clinical use so far [ 2 ]. The decreased expression of EGFR on the normal epithelium such as the skin and gastrointestinal tract results in on-target/off-tumor toxicity and lowers the dose of ITs available to target tumors, contributing to challenges in its applicability [ 2 , 3 ].…”

Section: Introductionmentioning

confidence: 99%

Expanding the Therapeutic Window of EGFR-Targeted PE24 Immunotoxin for EGFR-Overexpressing Cancers by Tailoring the EGFR Binding Affinity

Jun

Kim

2022

IJMS

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Immunotoxins (ITs), which are toxin-fused tumor antigen-specific antibody chimeric proteins, have been developed to selectively kill targeted cancer cells. The epidermal growth factor receptor (EGFR) is an attractive target for the development of anti-EGFR ITs against solid tumors due to its overexpression on the cell surface of various solid tumors. However, the low basal level expression of EGFR in normal tissue cells can cause undesirable on-target/off-tumor toxicity and reduce the therapeutic window of anti-EGFR ITs. Here, based on an anti-EGFR monobody with cross-reactivity to both human and murine EGFR, we developed a strategy to tailor the anti-EGFR affinity of the monobody-based ITs carrying a 24-kDa fragment of Pseudomonas exotoxin A (PE24), termed ER-PE24, to distinguish tumors that overexpress EGFR from normal tissues. Five variants of ER-PE24 were generated with different EGFR affinities (KD ≈ 0.24 nM to 104 nM), showing comparable binding activity for both human and murine EGFR. ER/0.2-PE24 with the highest affinity (KD ≈ 0.24 nM) exhibited a narrow therapeutic window of 19 pM to 93 pM, whereas ER/21-PE24 with an intermediate affinity (KD ≈ 21 nM) showed a much broader therapeutic window of 73 pM to 1.5 nM in in vitro cytotoxic assays using tumor model cell lines. In EGFR-overexpressing tumor xenograft mouse models, the maximum tolerated dose (MTD) of intravenous injection of ER/21-PE24 was found to be 0.4 mg/kg, which was fourfold higher than the MTD (0.1 mg/kg) of ER/0.2-PE24. Our study provides a strategy for the development of IT targeting tumor overexpressed antigens with basal expression in broad normal tissues by tailoring tumor antigen affinities.

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LncRNA ABHD11-AS1 promotes tumor progression in papillary thyroid carcinoma by regulating EPS15L1/EGFR signaling pathway

Zhu

Chen

et al. 2022

Clin Transl Oncol

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Preparation of a novel EGFR specific immunotoxin and its efficacy of anti-colorectal cancer in vitro and in vivo

Cited by 5 publications

References 54 publications

Nanobody-Based EGFR-Targeting Immunotoxins for Colorectal Cancer Treatment

Nanobody-Based EGFR-Targeting Immunotoxins for Colorectal Cancer Treatment

Expanding the Therapeutic Window of EGFR-Targeted PE24 Immunotoxin for EGFR-Overexpressing Cancers by Tailoring the EGFR Binding Affinity

LncRNA ABHD11-AS1 promotes tumor progression in papillary thyroid carcinoma by regulating EPS15L1/EGFR signaling pathway

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