Cancer biologics made in plants

Highlights

• Plant overexpression systems facilitate preclinical biologics development.

• Plants have been used to produce many protein vaccines, mAbs, and immunotherapeutics.

• Plant virus nanoparticles are effective cancer-targeting agents.

• Plant-derived lectins and lectibodies may have unique anti-cancer potential.

Plants are routinely utilized as efficient production platforms for the development of anti-cancer biologics leading to novel anti-cancer vaccines, immunotherapies, and drug-delivery modalities. Various biosimilar/biobetter antibodies and immunogens based on tumor-associated antigens have been produced and optimized for plant expression. Plant virus nanoparticles, including those derived from cowpea mosaic virus or tobacco mosaic virus in particular have shown promise as immunotherapies stimulating tumor-associated immune cells and as drug carriers delivering conjugated chemotherapeutics effectively to tumors. Advancements have also been made toward the development of lectins that can selectively recognize cancer cells. The ease at which plant systems can be utilized for the production of these products presents an opportunity to further develop novel and exciting anti-cancer biologics.

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.