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A Review of Therapeutic Antibodies in Breast Cancer

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A Review of Therapeutic Antibodies in Breast Cancer J Pharm Pharm Sci (www.cspsCanada.org) 24, 363 -380, 2021 A Review of Therapeutic Antibodies in Breast Cancer Maryam Eini1, Nahid Zainodini1, Hamed Montazeri2, Parastoo Mirzabeigi3, Parastoo Tarighi1 1Department of Medical Biotechnology, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran; 2School of Pharmacy-International Campus, Iran University of Medical Sciences, Tehran, Iran; 3Clinical Pharmacy Department, School of Pharmacy, Iran University of Medical Sciences, Tehran, Iran Corresponding authors: Parastoo Tarighi, Department of Medical Biotechnology, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran; TEL: +989122713060; email: [email protected]; Parastoo Mirzabeigi, Clinical Pharmacy Department, School of Pharmacy, Iran University of Medical Sciences, Tehran, Iran; TEL:+989123420796 email: [email protected] Received, May 11, 2021; Revised, July 13, 2021; Accepted. July 14, 2021; Published, July 21, 2021 ABSTRACT-- Since the first production of monoclonal antibodies about 35 years ago, researchers have found them useful in the treatment and diagnosis of various diseases such as cancer. By developing different types of monoclonal antibodies such as humanized, drug conjugated, or bispecific ones, researchers, have achieved remarkable success in treating several complicated and challenging diseases, targeting specific antigens or receptors makes monoclonal antibodies the right choice to inhibit signaling pathways like programmed death- ligand 1 (PD-L1) or programmed death1 (PD-1) and changing cell behavior. As one of the most common types of malignancies among women, breast cancer is one of the most critical conditions which different types of monoclonal antibodies were designed and produced to treat. Therefore, we reviewed these antibodies in breast cancer, their targets, and their efficacy and toxicity, with more focus on recent PD-L1or PD-1 inhibitor antibodies in breast cancer and beyond. INTRODUCTION improving the patient's survival, and decreasing the tumor relapse (5,6). By targeting a particular marker, According to the American Cancer Society, breast monoclonal antibodies are considered one of the cancer is among the four most frequent cancers; the most practical and promising approaches (7). For four being those of lung, colorectal, breast, and example, based on the reports in early-stage HER2+ prostate (1). It is estimated that 276,480 new cases breast cancer, the patients are treated with will be diagnosed with breast cancer in 2020 in the trastuzumab plus chemotherapy, the risk of disease United States of America (2). The global incidence recurrence and death decreased about 52% and 33%, of breast cancer is approximately 2.3 million cases in respectively, compared to the patients with 2020, and breast cancer as the most frequent administration of chemotherapy alone (8). malignancy among women surpassed lung cancer In general, monoclonal antibodies are (3). According to the International Agency for biomolecules which are capable of targeting a Research on Cancer (IARC), the rate of women's particular antigen. The first product of this class death due to breast cancer was 684,996 cases approved by the United States Food and Drug worldwide in 2020. As a leading cause of female Administration (FDA) in the late 1980s, was OKT3, cancer death, breast cancer accounted for about a murine anti-CD3 monoclonal antibody which was 15.5% of total cancer-related deaths in women (3). indicated for the treatment of organ transplant Although these figures indicate the severity of breast rejection (9). Along with developing cancer risk among women, its lethal rate has biotechnological techniques, the structure of decreased by 1.8% per year from 2007 to 2016 due monoclonal antibodies was evolved from murine, to the improvements in early detection and treatment chimeric, and humanized antibodies to fully human stages. Accordingly, the main treatment patterns are antibodies through recombinant DNA, transgenic, surgery, radiation therapy, chemotherapy, hormone and phage display technologies (10). In this manner, therapy, and targeted therapy (4). Targeted therapy is the issues such as the incomplete binding of human one of the approaches which usually help treatments Fc receptors and Fc region of murine by increasing the specificity of cancer therapy, immunoglobulins, development of human anti- 263 J Pharm Pharm Sci (www.cspsCanada.org) 24, 363 -380, 2021 mouse antibodies, and clearance of murine receptors) (16). Targeted breast cancer therapy can antibodies could be resolved (11,12). Different be performed by interfering with one of the monoclonal antibodies' mechanisms have been molecules of cancerous cells due to the type of breast proposed depending on the molecular characteristics cancer such as HER2. However, there is a recent such as cytotoxicity, modification of immune approach inhibiting the immune checkpoint by signaling, cellular activation/ interactivity, limitation different antibodies (22). Conjugation of antibodies of growing and proliferation, and foreign entities with drugs is the other treatment approach (23). In deactivation (13). this article, different types of monoclonal antibodies, Over the last two decades, monoclonal from the most common monoclonal antibodies to antibodies have become an interesting therapeutic treat breast cancer to more recently developed ones, option to treat different types of breast cancer as illustrated in Figure 1, will be overviewed . because of their specific targeting ability and overall response rate (14,15). Breast cancer has different COMMON THERAPEUTIC ANTIBODIES histological or molecular subtypes. Gene expression AGAINST BREAST CANCER profiling studies are the main determinants of molecular subtypes. The groups of genes which the Harboring overexpression of human epidermal molecular classification of breast cancer is done growth factor receptor 2 (HER2) is observed in about based on their overexpression are estrogen receptor 15-20% of breast cancer patients, making HER2 a (ER), progesterone receptor (PR), and members of potential target in developing therapeutic epidermal growth factor receptor (EGFR) family of approaches. In this way, many monoclonal receptor tyrosine kinases, including HER2 (Human antibodies were produced that target HER2. epidermal growth factor receptor 2) and EGFR Trastuzumab (Herceptin), as the first HER2 targeting (16,17). ER and PR are two hormone receptors (HR) approved humanized monoclonal antibody (IgG1), is that drive breast cancer progression (18). ER is considered for HER2 positive patients as first-line expressed in 75% of breast cancers overall and acts neoadjuvant therapy, in which a therapeutic agent is as a ligand-responsive transcription factor. administered before the main treatment such as Subsequent binding ER to its ligand, ERs dimerize surgery (24). Trastuzumab is prescribed for early- and get into the nucleus, where they bind to estrogen stage and metastatic cases (8,25). A recent study response elements (EREs) and stimulate showed that the combination therapy of trastuzumab transcription of genes related to cell proliferation and with capecitabine (a chemotherapy medication) and growth (18). Other proteins over-expressed in breast tucatinib (a small molecule inhibiting HER2) could cancer are epidermal growth factor receptors such as result in better overall survival in heavily pretreated HER2 and EGFR. All members have a similar patients who are suffering from HER2+ metastatic structure containing four extracellular domains, a breast cancer (15). transmembrane region, and an intracellular tyrosine Another FDA-approved neoadjuvant antibody kinase domain (19). Binding EGFR and HER2 is pertuzumab which targets the dimerization domain receptors to growth factors cause hetero or of HER2 (extracellular domain 2) and blocks homodimerization of receptors which activate the signaling pathways (26). In two APHINITY and autophosphorylation of intracellular tyrosine kinase CLEOPATRA trials, a combination of pertuzumab domain of the receptor. Phosphorylated tyrosine with trastuzumab plus chemotherapy or docetaxel kinase domain drives different signaling pathways improved invasive disease-free survival (DFS) and such as PI3K/AKT/TOR, RAS/MAPK, JAK/STAT, prolonged median overall survival (OS) by 15.7 and phospholipase Cγ (PLCγ), which lead to months, respectively (27,28). Understanding tumorigenesis and cellular proliferation (20, 21). interaction between tumors and immune system has Based on overexpression or lack of mentioned resulted to design and develop a new type of HER2- receptor proteins, breast cancer is categorized into targeting antibodies. Margetuximab as a recent anti- some molecular subtypes, including HR+ (defined HER2 chimeric IgG monoclonal antibody with by overexpression of hormone receptors like engineered Fc binds to CD16A by more high affinity. estrogen or/and progesterone receptor), EGFR, and CD16A is an Fc-receptor on immune cells, which HER2+ (defined by overexpression of the family of plays a role in antibody-dependent cell-mediated epidermal growth factor receptor), and triple- cytotoxicity. In 78% of response-evaluable patients negative breast cancer (defined by a lack of the receiving margetuximab, tumor reduction was expression of estrogen, progesterone, and the HER2 364 J Pharm Pharm Sci (www.cspsCanada.org) 24, 363 -380, 2021 observed; however, treatment has constitutional has evidence of intestinal perforation which is symptoms such as pyrexia, nausea,
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