Cancer biologics made in plants
Graphical abstract
Introduction
The 1997 approval of rituximab, which was the first anti-cancer monoclonal antibody (mAb) approved for use in the U.S., began a biologic explosion that has transformed the landscape of cancer therapy and dramatically altered and improved patient survival and quality of life. According to the U.S. National Cancer Institute (URL: https://www.cancer.gov/about-cancer/treatment/types/immunotherapy/bio-therapies-fact-sheet), this broad category of pharmaceuticals include immune checkpoint inhibitors, immune cell therapy, therapeutic mAbs and other immune system molecules, therapeutic vaccines and immune system modulators, which now combined make up the majority of total pharmaceutical sales globally (with a market value of approximately 1 trillion dollars in 2016) [1]. Since 1997 hundreds of biologic drugs have been approved or clinically evaluated, and the development of mAbs targeting immune checkpoints like PD-1 and CTLA-4 was even the subject of the 2018 Nobel Prize in Medicine or Physiology, a testament to the impact that biologics have had on medicine. Despite their promise, biologic drugs remain expensive due to manufacturing costs and the lack of significant generic competition from biosimilars (the first was only approved in 2015) [2]. Cell-culture based manufacturing systems are also slow to implement for initial screening and proof-of-concept (POC) studies, prolonging preclinical development of novel drugs, though alternative methods have some important advantages.
Cancer biologic production in plants has a long history, beginning with the early production of mAbs against tumor-associated antigens (TAAs) like CO17-A [3]. In contrast to transgenic plants, the recent advent of transient overexpression vectors allow relatively short time for novel biologic drugs to be produced at scale and tested, making plants an ideal platform for preclinical biologic development [4]. A large number of recent advances in the field have come from the area of plant virus nanoparticles (PVNs), particularly those derived from cowpea mosaic virus (CPMV), tobacco mosaic virus (TMV), and potato virus X (PVX), which have shown efficacy as both immunostimulatory agents/therapeutic vaccines and as drug delivery modalities capable of delivering chemotherapy payloads to tumor sites in vivo. While much of the literature is dominated by these advancements, steps have also been made toward the development of recombinant cancer vaccines based on tumor antigens and anti-cancer lectins. This review sets out to catalog recent advancements in plant-made cancer biologics and their future.
Section snippets
Cancer vaccines and immunotherapy
The goal of cancer vaccination is to induce tumor-specific immunity and activate immune cells in the tumor microenvironment to elicit anti-cancer activity. Cancer vaccines are immunostimulatory agents that often make use of TAAs, which are antigens capable of distinguishing cancer and non-cancer tissue or antigens that are overexpressed in cancer tissues compared to normal tissue, such as epidermal growth factor receptor (EGFR) and its family in some cancers. One such example is human prostatic
Drug delivery and imaging
Considerable research has been conducted into novel drug delivery systems, with the goal of improving the pharmacokinetics and pharmacodynamics of small molecule and biologic drugs by affecting their absorption and distribution in the body. PVNs have been particularly attractive owing their ability to deliver larger payloads than antibody-drug conjugates, the relative ease at which they can be decorated with targeting ligands for tissue-specific delivery of drugs, the wide array of possible
Anti-cancer lectins
Lectins are a diverse group of carbohydrate-binding proteins that have garnered much interest for their potential immunomodulating and cancer-targeting abilities. In recent years, a great number of fungal and plant lectins with anti-cancer activity have been isolated, characterized, and described in the literature [45,46]. Plant lectins in particular have been historically important as alternative or adjuvant therapies for cancer especially in Europe, where arguably the most well-known is a
Conclusions
Transient expression of proteins in plants is a powerful method for the rapid, robust production of recombinant proteins, which will significantly facilitate the preclinical development of biosimilar, biobetter, and innovator anti-cancer proteins as well as vaccines. PVNs show promise as immunostimulatory agents, drug delivery platforms and imaging probes. Since aberrant protein glycosylation is a hallmark of cancer [61,62], plant-derived lectins and their derivatives such as ‘lectibodies’ may
Conflict of interest statement
Nothing declared.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgement
This work was in part funded by the National Institutes of Health (R21CA216447).
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