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Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
A novel shark VNAR antibody-based immunotoxin targeting TROP-2 for cancer therapy
Xiaozhi Xi1,2,3, Yanqing Wang2, Guiqi An2
1College of Marine Science and Biological Engineering, Qingdao University of Science and Technology, Qingdao 266042, China.
Abstract:
TROP-2, a tumor-associated antigen, has been implicated in the progression of various epithelial tumors. Due to its favorable expression profile, TROP-2 has emerged as a promising target for antibody-drug conjugates (ADCs) based anti-tumor therapies. Although ADCs have shown efficacy in cancer treatment, their application in solid tumors is hindered by their high molecular weight, poor tumor penetration, and release of cytotoxic molecules. Therefore, a recombinant immunotoxin was developed based on a shark-derived variable domain of immunoglobulin new antigen receptor (VNAR) antibody. VNARs are only one-tenth the size of IgG antibodies and possess remarkable tissue penetration capabilities and high stability. In this study, a shark VNAR phage display library was created, leading to the identification of shark VNAR-5G8 that targets TROP-2. VNAR-5G8 exhibited a high affinity and cellular internalization ability towards cells expressing high levels of TROP-2. Epitope analysis revealed that VNAR-5G8 recognizes a hidden epitope consisting of CRD and TY-1 on TROP-2. Subsequently, VNAR-5G8 was fused with a truncated form of Pseudomonas exotoxin (PE38) to create the recombinant immunotoxin (5G8-PE38), which exhibited significant anti-tumor activity in vitro and in vivo. Overall, this study highlights the promise of 5G8-PE38 as a valuable candidate for cancer therapy.
Insights
A novel recombinant immunotoxin targeting TROP-2 shows promise for cancer therapy. This shark antibody-derived immunotoxin, 5G8-PE38, demonstrates significant anti-tumor activity in vitro and in vivo.
Area of Science:
- Oncology
- Immunotherapy
- Biotechnology
Background:
- TROP-2 is a tumor-associated antigen driving epithelial tumor progression.
- Antibody-drug conjugates (ADCs) targeting TROP-2 show efficacy but face challenges in solid tumors.
- Limitations of ADCs include high molecular weight, poor tumor penetration, and cytotoxic payload release.
Purpose of the Study:
- To develop a novel anti-cancer therapeutic targeting TROP-2.
- To overcome the limitations of ADCs using a smaller, more penetrant modality.
- To evaluate the efficacy of a TROP-2-targeting recombinant immunotoxin.
Main Methods:
- Creation of a shark variable domain of immunoglobulin new antigen receptor (VNAR) phage display library.
- Identification and characterization of TROP-2-specific VNAR clone 5G8.
- Fusion of VNAR-5G8 with a truncated Pseudomonas exotoxin (PE38) to create the immunotoxin 5G8-PE38.
- Assessment of 5G8-PE38 anti-tumor activity in vitro and in vivo.
Main Results:
- VNAR-5G8 demonstrated high affinity and cellular internalization for TROP-2-expressing cells.
- VNAR-5G8 recognizes a hidden epitope (CRD and TY-1) on TROP-2.
- The recombinant immunotoxin 5G8-PE38 exhibited significant anti-tumor activity against solid tumors.
Conclusions:
- Shark VNAR antibodies offer advantages in size and tissue penetration for cancer therapy.
- The TROP-2-targeting immunotoxin 5G8-PE38 is a promising candidate for novel cancer treatments.
- This approach may overcome limitations associated with traditional ADCs in solid tumor therapy.
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