Mini-reviewTargeted biopharmaceuticals for cancer treatment
Introduction
Cancer causes a significant mortality rate worldwide and its incidence is associated with the mutual interaction of oncogenes, tumor suppressor gene mutations and environmental toxins [44]. Cancer cells are usually characterized by multiple hallmarks, such as enhanced proliferation, reduced apoptosis and abnormal metabolic activity [29], [32], [33]. In order to effectively control the malignant transformation of cancer cells, it is very important to understand the mechanisms underlying the autonomous tumor cell growth. Thus, intensive efforts have been made to investigate the gene, protein, metabolite, and signaling pathway associated with cancer cell growth [73], [34], [63]. These studies have discovered specific targets, such as antigens or pathways, which benefit the development of anticancer therapies [78], [80].
Among the present cancer therapies, targeted anticancer biopharmaceuticals (e.g., monoclonal antibodies (mAbs), non-antibody proteins, and small molecules) have been demonstrated to efficiently control the progression of multiple cancers and significantly improve the life quality and overall survival of cancer patients. These biopharmaceuticals have usually been developed to target the specific antigen or signaling pathway involved in cancer progression. Of them, the mAb-based therapeutic protein is the fastest growing segment. More than a dozen innovative mAbs have been approved by the United States Food and Drug Administration (FDA) and the European Medicine Evaluation Agency (EMEA). A significant number of innovative non-antibody proteins and small molecule-based biopharmaceuticals are also available for cancer therapy. More recently, some generic biologics have been developed, approved, and applied to treat cancer in Europe and Asia.
Despite all the achievements in anticancer biopharmaceuticals development, without considering the heterogeneity of individual patients traditional drugs could cause various adverse side effects. The advances in Omics technologies enable the development of personalized medicines to overcome this issue. Improving clinical efficiency is another challenge in biopharmaceutical development. For instance, to maintain therapeutic concentration in human serum (typically >10 μg/mL), the dosage of mAb for a cancer patient is over several hundred milligrams per week [56]. The incomplete post-translational modifications (PTMs) of glycoprotein could reduce the quality of anticancer drugs and increase drug dosage. A biopharmaceutical with high clinical efficiency can be achieved by developing effective biopharmaceutical bioprocessing.
In this article, we first discuss specific antigens and core pathways identified in cancer cells that could be targeted to kill cells; then review the innovative and generic targeted therapeutic proteins, including monoclonal antibodies, non-antibody proteins and small molecule drugs marketed in US, EU and Asia; and finally describe the issues in anticancer biopharmaceuticals development and discuss the potential solutions to overcome these issues to achieve higher efficiency of cancer treatment.
Section snippets
Specific targets in cancer treatment
Targeting epigenetically and genetically abnormal molecules (e.g. antigens), or pathways, using biopharmaceuticals is an efficient strategy in cancer treatment. The currently identified antigens and pathways are reviewed below.
Innovative anticancer biopharmaceuticals
A significant amount of biopharmaceuticals, such as monoclonal antibodies (mAbs), non-antibody proteins and small molecules, have been developed and applied to treat various cancers [82]. As shown in Fig. 1, the anticancer biopharmaceuticals are used to treat multiple cancers because they can target the core pathway, antigen or regulator that is identified in various cancers. For instance, eight mAbs targeting different CD antigens have been developed to treat non-hodgkin’s lymphoma (NHL),
Generic biologics
According to the FDA draft guideline, generic biologics (a.k.a. biosimilar) refer to the biopharmaceuticals that are “highly similar to the reference innovative product, notwithstanding minor differences in clinically inactive components” [1], [16], [60]. Generic drugs are manufactured and marketed after the patents of the existing innovative biopharmaceuticals are expired. The utilization of generic biologics can significantly lower the clinical cost. The EMEA approved the first biosimilar,
Challenges and strategies
As discussed above, a number of effective targeted biopharmaceuticals have been successfully applied in cancer treatment, but there are still challenges in anticancer drugs development such as high side effects, low bioactivity, high dosage, and immunogenic response. Some major issues and the potential solutions are discussed below.
Conclusion and perspective
The application of targeted anticancer biopharmaceuticals has greatly improved the treatment of cancers. The success of anticancer therapeutic drug development is built on decades of fundamental research and clinical diagnosis that investigate the oncogene, signaling pathway and core pathway relevant to cancer prognosis. The deep understanding of the complex interplay between cancer cells and the immune system has generated optimized antibodies and other proteins. In addition, the advanced
Conflicts of interest
The authors declare that no conflicting of interest exists.
Acknowledgements
The authors would like to thank Nicole Rivas and Ryan Bollenbach for editing this manuscript and correcting the language errors. This work was supported by the start up fund from The University of Alabama and sponsored by the BRIGE Grant (24512) from the National Science Foundation.
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2021, Chinese Journal of Chemical EngineeringCitation Excerpt :After binding, the ADC is internalized via receptor-mediated endocytosis, a late endosome is formed, and lysosomal degradation releases cytotoxic drug into the cytoplasm, ultimately leading to cancer cell death [92]. Multiple ADCs have been developed to effectively treat cancers in clinics while minimizing side effects in normal cells [93–99]. Here we use three FDA approved ADCs as examples to describe the construction, anti-cancer mechanisms, and clinical applications of this mAb-directed therapy.
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