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Glycosylation of Recombinant Anticancer Therapeutics in Different Published OnlineFirst May 22, 2018; DOI: 10.1158/0008-5472.CAN-18-0032 Cancer Review Research Glycosylation of Recombinant Anticancer Therapeutics in Different Expression Systems with Emerging Technologies Tariq Nadeem1, Mohsin Ahmad Khan1, Bushra Ijaz1, Nadeem Ahmed1, Zia ur Rahman1, Muhammad Shahzad Latif1, Qurban Ali1,2, and Muhammad Adeel Rana3 Abstract Glycosylation, a posttranslational modification, has a major system to obtain structurally and functionally identical glycans, role in recombinant anticancer therapeutic proteins, as most of as in humans. In many expression systems, the N-glycosylation the approved recombinant therapeutics are glycoproteins. The pathway remains conserved in the endoplasmic reticulum, constant amino acid sequence of therapeutics determines the but divergence is observed when the protein enters the Golgi enzymatic activity, while the presence of glycans influences complex. Hence, in recent decades, numerous approaches their pharmacokinetics, solubility, distribution, serum half-life, have been adopted to engineer the Golgi's N-glycosylation effector function, and binding to receptors. Glycoproteins pathway to attain human-like glycans. Several researchers have expressed in different expression systems acquire their own tried to engineer the N-glycosylation pathway of expression oligosaccharides, which increases the protein diversity. The systems. In this review, we examine the glycosylation pattern heterogeneity of glycans creates hurdles in downstream proces- in various expression systems, along with emerging technologies sing, ultimately leading to variable anticancer therapeutic effi- for glycosylation engineering of anticancer therapeutic drugs. cacy. Therefore, glycoproteins require an appropriate expression Cancer Res; 78(11); 1–12. Ó2018 AACR. Introduction ket value of protein-based drugs is growing, with a compounded annual growth rate of 16% compared with the pharmaceutical Cancer is the second leading cause of death in humans, devour- market growth rate of 8% (9). Among the total approved bio- ing the lives of 8.8 million people in 2015 (1, 2). In 2025, 19.3 pharmaceuticals, almost 70% are glycoproteins, which contain million new cases are predicted (3). This disease is characterized carbohydrate moieties gained as a posttranslational modification by abnormal and uncontrolled growth of cells, which have the in the process of glycosylation (10–13). This glycosylation diver- potential to invade other parts of the body through metastasis sifies the class of biopharmaceuticals. Many functions of antican- (4, 5). Currently, most common cancer treatments include cer glycoproteins are associated with glycan attachments, such as radiotherapy, surgery, and chemotherapy. With the advancement solubility, pharmacodistribution, pharmacokinetics, proper of technologies, efforts are being made in clinical treatment to structural folding, binding to receptors, and serum half-life (14). identify effective state-of-the-art therapies to replace conventional The most significant anticancer therapeutic recombinant pro- methods (6, 7). teins are mAbs, which are glycosylated in their Fc region (15). Recent advances have paved the way for the development of Alteration of the composition and structure of glycans causes recombinant anticancer therapeutics through engineered cell conformational changes in the Fc domain of antibodies, affecting lines. As anticancerous agents, these drugs improve the delivery their binding affinity to Fcg receptors (16, 17). This process leads of immune cells to tumor tissues, altering the tumor microenvi- to a change in immune effector functions, including complement- ronment, enhancing antigen priming, and facilitating effector cell dependent cytotoxicity, antibody-dependent cell-mediated cyto- activation and maturation (6, 7). Production of anticancer ther- toxicity (ADCC), and antibody-dependent cell-mediated phago- apeutic proteins as a class of drugs is dominating the drug cytosis (18). Deglycosylation of antibodies reduces their binding industry, partly because of the high demand and partly because affinity and hence their effector functions (19, 20). Changes in the of advancements in recombinant DNA technology (8). The mar- glycoforms of therapeutic mAbs or Fc-fusion proteins can impact the pharmacokinetics of proteins; for example, the negative impact of hypermannosylation on pharmacokinetics can trigger 1Center of Excellence in Molecular Biology, University of the Punjab, Lahore, the C-type lectin clearance mechanism (15, 18, 21). In many cases, Pakistan. 2Institute of Molecular Biology and Biotechnology, University of the terminal sugars in the glycans can affect the pharmacokinetics 3 Lahore, Lahore, Pakistan. Department of Microbiology, Quaid-I-Azam Univer- of an antibody due to glycan binding to receptors on tissues, sity, Islamabad, Pakistan. ultimately leading to its removal from circulation. The major Corresponding Authors: Qurban Ali, Center of Excellence in Molecular Biology, glycan receptors that remove glycoproteins are the mannose University of the Punjab, Lahore 57300, Pakistan. Phone: 321-962-1929; E-mail: receptor and the asialoglycoprotein receptor (22, 23). As both [email protected]; and Tariq Nadeem, [email protected] these receptors are abundantly expressed in the liver, it is likely doi: 10.1158/0008-5472.CAN-18-0032 that glycoproteins with terminal mannose or galactose residues Ó2018 American Association for Cancer Research. will be distributed predominantly in the liver and be catabolized www.aacrjournals.org OF1 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst May 22, 2018; DOI: 10.1158/0008-5472.CAN-18-0032 Nadeem et al. there, as shown by Wright and colleagues in the case of an IgG with their effector functions. This article reviews N-glycosylation occur- terminal mannose or galactose residues (24). ring in different expression systems, and we have summarized the Development of recombinant anticancer therapeutics has various strategies adopted in different glycosylation engineering made substantial progress for the treatment of various solid and technologies. hematologic tumors over the past decade (25–27). Naked mAbs are most commonly used to treat cancer. Rituximab was the first N-glycosylation in the Endoplasmic fi recombinant mAb approved by FDA in 1997 and nds its ther- Reticulum apeutic applications in variety of hematologic cancers including lymphocytic leukemia and non-Hodgkin lymphoma. It is an Eukaryotic N-glycosylation occurs in two organelles, the endo- anti-CD20 humanized recombinant drug that plays a pivotal role plasmic reticulum (ER) and the Golgi complex. Dolichol-linked in B-cell malignancies (28–30). On the other hand, trastuzumab glycan precursor formation and transfer to a nascent protein with is one of the mAbs used for the treatment of solid tumor that is a little bit of processing occurs in the ER, while complete matu- þ capable of ADCC through interactions with Fcg/R immune cell ration and processing of N-linked glycans occurs in the Golgi subsets. It has transformed the treatment of HER-2–positive breast apparatus. N-glycosylation occurs at asparagine residue in the cancer (31–33). Tumor targeted recombinant mAbs can also be consensus amino acid sequence (Asn-X-Ser/Thr), where X can be conjugated to other forms of anticancer therapy that enhances any amino acid, but not proline. The process is initially started and their efficacy by lessening the systemic toxicities to normal cells. processed in the ER, where oligosaccharide transferase (OT) There are three types conjugated mAbs: radiolabeled that are catalyzes the transfer of glycan onto the nascent protein (48). attached to radionuclide moieties, chemolabeled that are linked Secretory proteins containing signal peptides are directed by to antineoplastic drugs, and immunotoxin mAbs that are associ- signal recognition particles across the membrane into the lumen ated with bacterial and plant toxins (34–36). Revolution in of the ER, followed by its movement into the OT-mediated recombinant DNA technology has facilitated the progress toward glycosylation machinery. Glycosylation is not dependent on more specific and less toxic anticancer therapy (29). protein folding or tertiary structure. However, some evidence has In eukaryotic organisms, N-glycosylation is the most prevalent shown that secondary structures on both sides of the Asn con- type of glycosylation, in which a preassembled oligosaccharide is sensus sequences may help in this enzymatic reaction (48). The transferred onto asparagine (Asn) in the consensus sequence of whole process of glycosylation is completed in the ER and Golgi the nascent protein. This oligosaccharide processing and matu- bodies. Glycoproteins processed in the ER usually show homol- ration occurs regardless of the protein template (12, 37–40). ogy and remain conserved in higher eukaryotes and yeast (49). Hence, cancer glycoproteins expressed in different expression Tetradecasaccharide (Glc3Man9GlcNAc2b1) attached to Asn- systems acquire glycans depending on their own glycosylation amide groups is derived from the dolichol pathway (50). The machinery. Glycoproteins expressed in yeast show hypermanno- synthesis of tetradecasaccharide starts on the cytosolic face of the sylated glycans, which compromise their therapeutic efficacy ER by transferring GlcNAc onto the membrane-anchored Dol-P, (41–45). Similarly, glycoproteins expressed in plant cells acquire
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