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A Novel Approach to Anticancer Therapy: Molecular Modules Based on the Barnase:Barstar Pair for Targeted Delivery of
A M Sapozhnikov1, A V Klinkova1, O A Shustova1
1Shemyakin - Ovchinnikov Institute of Bioorganic Chemistry RAS, Miklukho-Maklaya Str., 16/10, Moscow, 117997, Russia.
Abstract:
One important distinction between many tumor cell types and normal cells consists in the translocation of a number of intracellular proteins, in particular the 70 kDa heat shock protein (HSP70), to the surface of the plasma membrane. It has been demonstrated that such surface localization of HSP70 on tumor cells is recognized by cytotoxic effectors of the immune system, which increases their cytolytic activity. The mechanisms behind this interaction are not fully clear; however, the phenomenon of surface localization of HSP70 on cancer cells can be used to develop new approaches to antitumor immunotherapy. At the same time, it is known that the presence of HSP70 on a cell's surface is not a universal feature of cancer cells. Many types of tumor tissues do not express membrane-associated HSP70, which limits the clinical potential of these approaches. In this context, targeted delivery of exogenous HSP70 to the surface of cancer cells with the aim of attracting and activating the cytotoxic effectors of the immune system can be considered a promising means of antitumor immunotherapy. Molecular constructs containing recombinant mini-antibodies specific to tumor-associated antigens (in particular, antibodies specific to HER2/neu-antigen and other markers highly expressed on the surface of a wide range of cancer cells) can be used to target the delivery of HSP70 to tumor tissues. In order to assess the feasibility and effectiveness of this approach, recombinant constructs containing a mini-antibody specific to the HER2/ neu-antigen in the first module and HSP70 molecule or a fragment of this protein in the second module were developed in this study. Strong selective interaction between the modules was ensured by a cohesive unit formed by the barnase:barstar pair, a heterodimer characterized by an unusually high constant of association. During testing of the developed constructs in in vitro models the constructs exhibited targeted binding to tumor cells expressing the HER2/neu antigen and the agents had a significant stimulating effect on the cytotoxic activity of NK cells against the respective cancer cells.
Insights
This study developed novel constructs to deliver heat shock protein 70 (HSP70) to cancer cells, enhancing immune cell activity against tumors. This approach targets HER2/neu-expressing cells, potentially improving immunotherapy for cancers lacking natural HSP70 surface expression.
Area of Science:
- Immunology
- Molecular Biology
- Biotechnology
Background:
- Intracellular proteins like heat shock protein 70 (HSP70) can translocate to the surface of tumor cells, enhancing immune recognition and cytolytic activity.
- Surface HSP70 on cancer cells presents a potential target for immunotherapy, but its expression is not universal across all tumor types.
- Targeted delivery of exogenous HSP70 to cancer cell surfaces offers a strategy to activate immune responses against tumors that lack endogenous membrane-associated HSP70.
Purpose of the Study:
- To develop and evaluate novel molecular constructs for targeted delivery of HSP70 to cancer cells.
- To assess the ability of these constructs to attract and activate cytotoxic immune cells, specifically NK cells.
- To investigate the feasibility of using mini-antibodies targeting tumor-associated antigens like HER2/neu for directed HSP70 delivery.
Main Methods:
- Construction of recombinant molecules featuring a mini-antibody specific to HER2/neu and an HSP70 moiety, linked by the high-affinity barnase:barstar system.
- In vitro testing of the constructs for targeted binding to HER2/neu-expressing tumor cells.
- Evaluation of the constructs' effect on natural killer (NK) cell-mediated cytotoxicity against target cancer cells.
Main Results:
- The developed constructs demonstrated selective binding to tumor cells expressing the HER2/neu antigen.
- The constructs significantly stimulated NK cell cytotoxic activity against the targeted cancer cells.
- This indicates the potential of engineered HSP70 delivery for enhancing antitumor immunity.
Conclusions:
- Engineered molecular constructs can effectively deliver HSP70 to specific cancer cell surfaces.
- This targeted delivery approach enhances the cytotoxic activity of immune cells like NK cells against cancer.
- This strategy holds promise for developing new immunotherapies for cancers, particularly those with limited natural surface HSP70 expression.
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