Novel recombinant immunotoxin of EGFR specific nanobody fused with cucurmosin, construction and antitumor efficiency<i>in vitro</i>

Deng, Cuimin; Xiong, Jiani; Gu, Xiaofan; Chen, Xiaoying; Wu, Shuifa; Wang, Zhe; Wang, Duanduan; Tu, Jinjin; Xie, Jianping

doi:10.18632/oncotarget.16930

Cited by 40 publications

(30 citation statements)

References 60 publications

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“…Unfortunately, we did not find a renal cancer cell line that does not express EGFR. Therefore, we used EGFR-negative colon cancer cell lines SW620 and HT-29 as control target cells in the following experiments ( Figure 2 ) [ 47 , 48 ].…”

Section: Resultsmentioning

confidence: 99%

Synergistic Effects of Cabozantinib and EGFR-Specific CAR-NK-92 Cells in Renal Cell Carcinoma

Zhang

Tian

Xǔ

et al. 2017

Journal of Immunology Research

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The chimeric antigen receptor-modified immune effector cell (CAR-T and CAR-NK) therapies are newly developed adoptive treatments of cancers. However, their therapeutic efficacy against solid tumors is limited. Combining CAR-T or CAR-NK cells with chemotherapeutic drugs to treat solid tumor may be a promising strategy. We developed an epidermal growth factor- (EGFR-) specific third-generation CAR. NK-92 cells were modified with the CAR by lentivirus infection. The specific killing ability of the CAR-modified NK-92 cells (CAR-NK-92) against renal cell carcinoma (RCC) cell lines was confirmed in vitro. The synergistic effects of cabozantinib and EGFR-specific CAR-NK-92 cells were investigated in vitro and in vivo. Our results showed that the CAR-NK-92 cells lyse RCC cells in an EGFR-specific manner. Treatment with cabozantinib could increase EGFR and decrease PD-L1 membrane surface expression in RCC cells and enhance the killing ability of CAR-NK-92 cells against the RCC cells in vitro. Furthermore, the CAR-NK-92 cells show synergistic therapeutic efficacy with cabozantinib against human RCC xenograft models. Our results provided the basis for combination with chemotherapy as a novel strategy for enhancing the therapeutic efficacy of CAR-modified immune effector cells for solid tumors.

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Section: Resultsmentioning

confidence: 99%

Synergistic Effects of Cabozantinib and EGFR-Specific CAR-NK-92 Cells in Renal Cell Carcinoma

Zhang

Tian

Xǔ

et al. 2017

Journal of Immunology Research

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“…And CD7-specific nanobodies fused to PE38 showed cytotoxic efficacy in CD7-expressing T-cell acute lymphoblastic leukemia in vitro and in a preclinical mouse model in vivo ( 91 , 92 ). Genetic fusion of an anti-EGFR nanobody to cucurmosin, a pumpkin toxin from the family of type 1 ribosome inactivating proteins induced cell death of EGFR-expressing cells lines in vitro ( 93 ).…”

Section: Nanobody-based Immunotoxinsmentioning

confidence: 99%

Nanobodies and Nanobody-Based Human Heavy Chain Antibodies As Antitumor Therapeutics

Bannas¹,

2017

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Monoclonal antibodies have revolutionized cancer therapy. However, delivery to tumor cells in vivo is hampered by the large size (150 kDa) of conventional antibodies. The minimal target recognition module of a conventional antibody is composed of two non-covalently associated variable domains (VH and VL). The proper orientation of these domains is mediated by their hydrophobic interface and is stabilized by their linkage to disulfide-linked constant domains (CH1 and CL). VH and VL domains can be fused via a genetic linker into a single-chain variable fragment (scFv). scFv modules in turn can be fused to one another, e.g., to generate a bispecific T-cell engager, or they can be fused in various orientations to antibody hinge and Fc domains to generate bi- and multispecific antibodies. However, the inherent hydrophobic interaction of VH and VL domains limits the stability and solubility of engineered antibodies, often causing aggregation and/or mispairing of V-domains. Nanobodies (15 kDa) and nanobody-based human heavy chain antibodies (75 kDa) can overcome these limitations. Camelids naturally produce antibodies composed only of heavy chains in which the target recognition module is composed of a single variable domain (VHH or Nb). Advantageous features of nanobodies include their small size, high solubility, high stability, and excellent tissue penetration in vivo. Nanobodies can readily be linked genetically to Fc-domains, other nanobodies, peptide tags, or toxins and can be conjugated chemically at a specific site to drugs, radionuclides, photosensitizers, and nanoparticles. These properties make them particularly suited for specific and efficient targeting of tumors in vivo. Chimeric nanobody-heavy chain antibodies combine advantageous features of nanobodies and human Fc domains in about half the size of a conventional antibody. In this review, we discuss recent developments and perspectives for applications of nanobodies and nanobody-based human heavy chain antibodies as antitumor therapeutics.

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“…Progress in genetic engineering has allowed the creation of recombinant antitumor agents where protein toxins of various origins and the mechanism of action are fused with a targeting moiety into a single polypeptide chain. The wide spectrum of recombinant antitumor agents specific to EGFR family receptors undergo clinical [171,172,173,174] and preclinical trials [131,135,136,175,176,177,178,179,180,181,182,183,184,185].…”

Section: Active Targetingmentioning

confidence: 99%

Targeted Delivery to Tumors: Multidirectional Strategies to Improve Treatment Efficiency

Kutova

Guryev

Соколова

et al. 2019

Cancers

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Malignant tumors are characterized by structural and molecular peculiarities providing a possibility to directionally deliver antitumor drugs with minimal impact on healthy tissues and reduced side effects. Newly formed blood vessels in malignant lesions exhibit chaotic growth, disordered structure, irregular shape and diameter, protrusions, and blind ends, resulting in immature vasculature; the newly formed lymphatic vessels also have aberrant structure. Structural features of the tumor vasculature determine relatively easy penetration of large molecules as well as nanometer-sized particles through a blood–tissue barrier and their accumulation in a tumor tissue. Also, malignant cells have altered molecular profile due to significant changes in tumor cell metabolism at every level from the genome to metabolome. Recently, the tumor interaction with cells of immune system becomes the focus of particular attention, that among others findings resulted in extensive study of cells with preferential tropism to tumor. In this review we summarize the information on the diversity of currently existing approaches to targeted drug delivery to tumor, including (i) passive targeting based on the specific features of tumor vasculature, (ii) active targeting which implies a specific binding of the antitumor agent with its molecular target, and (iii) cell-mediated tumor targeting.

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Novel recombinant immunotoxin of EGFR specific nanobody fused with cucurmosin, construction and antitumor efficiencyin vitro

Cited by 40 publications

References 60 publications

Synergistic Effects of Cabozantinib and EGFR-Specific CAR-NK-92 Cells in Renal Cell Carcinoma

Synergistic Effects of Cabozantinib and EGFR-Specific CAR-NK-92 Cells in Renal Cell Carcinoma

Nanobodies and Nanobody-Based Human Heavy Chain Antibodies As Antitumor Therapeutics

Targeted Delivery to Tumors: Multidirectional Strategies to Improve Treatment Efficiency

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