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MONOCLONAL ANTIBODIES: NEW THERAPEUTIC APPROACH IN TARGETED
TREATMENT
PRANAV GUPTA
General Medicine Student (Group 4030a), Karaganda Medical University, Karaganda,
Kazakhstan
SAARANSH CHAUDHARY
General Medicine Student (Group 4018a), Karaganda Medical University, Karaganda,
Kazakhstan
TIMUR BEISENOV, PUNIT KUMAR
Department of Morphology, Karaganda Medical University, Karaganda, Kazakhstan
Abstract. Monoclonal antibodies (mAbs) are immune proteins that bind specifically to antigens. These are producedfrom B lymphocytes and identify and neutralize the antigens. Antibodies perform the activities via agglutination, neutralization, fixation with activation of complement, and activation of effector cells. Though initial therapeutic uses of mAbs were used to target soluble cytokines, mAbs also target membrane-bound receptors. Monoclonal antibodies demonstrate multiple benefits such as; reduced adverse effects, high specificity, and higher efficiency. Monoclonal antibodies are used in the treatment of various diseases and research and development. The FDA approval of Orthoclone OKT3 as an antirejection agent for renal transplantation was a landmark in the medicinal use of monoclonal antibodies. It is recognized as first therapeutic antibody. The use of monoclonal antibodies for cancer treatment therapies started in 1997 when the first monoclonal antibody i.e. Rituximab was approved by the FDA for CD20+ B cell non-Hodgkin 's lymphoma. Even the mABs offer good prospects in therapeutics, these are structurally complex molecules and are susceptible to post-translational modification. This article will discuss the basic features of monoclonal antibodies and their applications.
Keywords: Monoclonal Antibodies; Antibody Drug Conjugates; Anticancer mAbs; Bispecific Antibodies
INTRODUCTION
Antibodies or immunoglobulin are specific types of proteins that are protective in nature and produced by the immune system in our body as a response to any foreign substance i.e. Antigen. The antibody is considered a secreted form of B cell receptor (Janeway et al., 2001). These are also termed plasma proteins and the sugar groups are added to the amino acids via the process of glycosylation which is also termed as O-linked glycosylation and N-linked glycosylation (Wootla et al., 2014).
A basic antibody is in Y shape and is composed of polypeptide chain pairs, two identical light chains, and two identical heavy chains linked together by disulfide linkages. The heavy chain is also linked to light chain by a disulfide bond. There are three portions i.e. variable portion, constant portion, and effector region. The variable portion of the antibody has antigen binding sites to which antigens bind and this variable portion connects to a constant portion at a hinge point where disulfide linkage is present. Together the heavy chains form the stem or central part of this Y shape and the light chains or smaller proteins act as arms of this Y shape. The generic term used for antibodies is immunoglobulin.
There are 5 main classes of antibodies which are IgG, IgM, IgA, IgD, and IgE, here Ig stands as an abbreviation to immunoglobulin. IgG is the most common antibody and most of the monoclonal antibodies are derived from IgG and it usually presents as a monomer, IgM is the biggest in size due to its pentameric form, IgA is usually or mainly a monomer but in secretions it is present as a dimmer form and IgD and IgE are also in monomer form but the difference in length of chains is present.
Another classification of antibodies is Monoclonal and Polyclonal which basically is according to the type of cloning of B cells. Monoclonal comes from a single B clone while the polyclonal comes from multiple clones of B-cell (Wootla et al., 2014). The specificity of monoclonal antibodies for antigens is high vs the polyclonal which has a wider range of antigen or epitope specificity. Due to the interaction of monoclonal antibodies with antigens, these are generally used in diagnostics, research, and targeted therapies.
IgG has a molecular weight of about 150 kDa. One heavy (H) chain contributes about 50 kDa, and the light (L) chain is comprised of about 25 kDa. In any given Ig molecule, the two heavy chains and the two light chains are identical, providing two similar antigen-binding sites to one antibody (Janeway et al., 2001).
Two light chain types, lambda (X) and kappa (k), are found in antibodies. One antibody has either k chains or X chains, never one of each. No functional difference is suggested between antibodies with k or X light chains. The structure of its heavy chain defines the class, and effector function of an antibody. There are five main heavy-chain classes or isotypes, and some of them may have several subtypes. The major types of heavy chains are denoted by p, 5, y, a, and s (Janeway et al., 2001).
The initial monoclonal antibodies were purely murine, later hybridoma technology, and recombinant DNA technology approaches were developed for production. Monoclonal antibodies can be categorized into four categories (based on the amount of mouse and human antibodies) such as; Murine monoclonal antibodies, Chimeric monoclonal antibodies, Humanized monoclonal antibodies, and Human monoclonal antibodies (Myhre and Sifris, 2023).
In this review article, we will discuss about different structural properties of monoclonal antibodies (mAbs), and the therapeutic and other applications of mAbs. Including this, the basic features of antibody-drug conjugates and bispecific antibodies are also discussed.
THERAPEUTIC APPLICATIONS OF MONOCLONAL ANTIBODIES (mAbs)
Blocking growth factor receptor signalling is the primary direct method by which many antibodies cause tumor cell death. When mAbs attach to their target growth factor receptors, they alter their activation state or prevent ligand binding, which disrupts pro-tumor growth and survival signalling.
mAb is not attached to any drug or radioactive material and is self-working, the most common type used for cancer treatment, the example is Rituximab (Rituxan) which is used in the treatment of some types of Non-Hodgkin Lymphoma or Trastuzumab (Herceptin) is an antibody that works against HER2 protein that is present in breast and stomach cancer cells in high amounts.
Monoclonal Antibodies in cancer treatment:
Monoclonal antibody-based immunotherapy is assumed to be a key component of anticancer treatment with chemotherapy, radiation, and surgery. Monoclonal antibodies are able to target cancer cells directly while simultaneously inducing anti-tumor immune responses (Zahavi and Weiner, 2020). The mechanisms of action of monoclonal antibodies mainly focus on the stimulation of a variety of innate immune effector processes, which is considered to be mainly responsible for the anticancer efficacy of most unconjugated mAb therapies (Tsao et al., 2021).
mAbs as a cancer treatment option offer a potentially high level of specificity and efficacy with a low level of off-target toxicity. mAbs specifically target cell surface antigens. These antigens may be overexpressed or selectively expressed in cancer cells, as well as proteins post-translationally changed that differentiate cancer cells from healthy cells.
Many monoclonal antibody therapies are recognized by the FDA. Here we are explaining the features of some monoclonal antibodies against cancer (Fig. 1).
6 О
Rituximab
Fig. 1: Some examples of monoclonal antibodies those are used in cancer treatment
Rituximab
The most common or popular mAbs is Rituximab which was approved by the Food and Drug Administration (FDA) in 1997 for a non-Hodgkin lymphoma orphan indication (Delate et al., 2020). It was the first mAb to get approved against cancer. Rituximab is a chimeric mouse/human monoclonal antibody treatment that binds to CD20. Since its initial approval in 1997, it has improved the outcomes in all B-cell malignancies, including follicular lymphoma, chronic lymphocytic leukemia, and diffuse large B-cell lymphoma (Pierpont et al., 2018). Some brand names of Rituximab are Rituxan, Riabni, Ruxience, and Truxima (National Cancer Institute, Rituximab, 2024).
Rituximab interacts with cell surface antigen CD20 of B-lymphocytes. The binding of Rituximab is associated with activation of complement-dependent B-cell cytotoxicity. The binding of Rituximab to human Fc receptors mediates cell death via antibody-dependent cellular toxicity (Medline, Rituximab, 2020).
Trastuzumab
Trastuzumab was approved in 1998, and it is a recombinant antibody against HER2. It was the first biological treatment approved for the treatment of HER2-positive breast cancer. Although other anti-HER2 agents are also available (e.g. lapatinib, and pertuzumab), trastuzumab remains the gold standard for the treatment of breast cancer (Maximiano et al., 2016). The US brand name of Trastuzumab includes; Ogivri, Herzuma, Herceptin, Kanjinti, Trazimera, Hercessi, and Ontruzant (National Cancer Institute, Trastuzumab, 2023). Furthermore, FDA approved the combination of tucatinib (Tukysa) and trastuzumab (Herceptin) for the treatment of advanced colorectal cancer producing an excess amount of HER2 proteins (Reynolds, 2023).
Cetuximab
Cetuximab was FDA approved in 2004. Cetuximab is a type of targeted cancer drug for the treatment of colorectal cancer (that has spread to other parts of the body), and Squamous cell carcinoma of the head and neck. Its brand name is Erbitux (National Cancer Institute, Cetuximab, 2023; Cancer Research UK, 2023).
Cetuximab targets the ligand-binding domain of the epidermal growth factor receptor and stops the downstream intracellular signals (Zhuang, 2011). Cetuximab is a recombinant humanized monoclonal antibody. It binds specifically to the epidermal growth factor receptor (EGFR, HER1, c-ErbB-1). It blocks phosphorylation and activation of receptor-associated kinases, which results into cell growth inhibition, induction of apoptosis, and reduced production of matrix metalloproteinase and vascular endothelial growth factor (VEGF) production (Medline, Cetuximab, 2020).
In Jul 2012, FDA approved the Erbitux (cetuximab) in combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) for the first-line treatment of candidates with KRAS mutation-negative (KRAS wild-type), EGFR expressing metastatic colorectal cancer (Leach, 2012).
Daratumumab
Daratumumab is FDA approved monoclonal antibody treatment for Multiple myeloma. It was approved by FDA in 2015 as monotherapy for patients with multiple myeloma who have received at least three prior lines of therapies, including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are double refractory to a PI and an immunomodulatory agent. In 2016, the FDA approved daratumumab (DARZALEX) in combination with bortezomib and dexamethasone, or lenalidomide and dexamethasone for multiple myeloma patients who have received at least one prior therapy (FDA, Daratumumab, 2016). Its brand name is Darzalex.
It has been found that daratumumab-based regimens are efficient treatment approaches across all lines of therapy, with the highest response rate in 1 Line (Atrash et al., 2021).
Daratumumab is a monoclonal antibody (IgG1k) that binds with the CD38 molecule, which is expressed on the cell surface of multiple myeloma cells. Binding to CD38 induces rapid cell death through apoptosis by Fc-mediated cross-linking and multiple immune-mediated mechanisms, including complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis, and antibody-dependent cellular cytotoxicity (Medline, Daratumumab, 2020).
Bevacizumab
Bevacizumab (Avastin) was first approved by FDA in 2004 (Stewart, 2021). It is a recombinant humanized monoclonal antibody that targets vascular endothelial growth factor A (VEGF-A). This antibody treatment is used for the treatment of several cancers (non-squamous non-small cell lung cancer, metastatic colorectal cancer, cervical cancer, glioblastoma, primary peritoneal cancer, ovarian epithelial, fallopian tube, and renal cell carcinoma) (Gerriets and Kasi, 2023; National Cancer Institute, Bevacizumab, 2023). Its brand names are Zirabev, Alymsys, Mvasi, Avastin (National Cancer Institute, Bevacizumab, 2023).
Bevacizumab performs its activity by interacting with VEGF which inhibits microvascular growth and angiogenesis that further regulates malignant cell growth and the formation of blood vessels. Bevacizumab is also suggested to improve the quality of life for patients suffering from Glioblastoma (Gil-Gil et al., 2013).
Conjugated Monoclonal Antibodies
These are also termed Antibody Drug Conjugates (ADCs). The ADCs are novel alternatives for cancer treatment. This new class of anticancer therapies contains coupling of antitumor monoclonal antibodies with cytotoxic drugs. ADCs offer several advantages of accurate target recognition, reduced toxicity to noncancerous healthy cells, and good tolerance (Liu et al., 2024).
In these conjugates, the mAbs are attached to small molecules (chemotherapy drugs, or radioactive material) with a linker. For ADC development, important factors are target antigen, cytotoxic payload, linker, antibody, and method of conjugation. ADC performs the activity through a mechanism; monoclonal antibodies interact with the target antigen, ADC-antigen conjugate enters into the cells, linker is cleaved by the activity of lysosomes, small molecule cytotoxic drugs are released, cytotoxic molecules exhibit cytotoxicity. In this process, antibodies also exhibit synergistic effects and they also perform as role of targeted drugs (BOC Sciences, 2024).
ADCs are mainly developed for cancer treatment but these molecules can be used against other diseases (Pettinato, 2021). These molecules provide selective delivery of cytotoxic payloads to tumors. For example, Brentuximab Vedotin (Adcetris) targets CD30 antigen. In 2011, Adcetris (Seattle Genetics) was approved by FDA for the treatment of Hodgkin's lymphoma and patients with systemic anaplastic large cell lymphoma (ALCL) (Younes et al., 2012).
However, to explore the full potential of this platform, there is a requirement of novel molecular designs to overcome many critical challenges such as; tumor heterogeneity, drug resistance, and adverse effects observed during the treatment. Several emerging ADC formats also exist such as; conditionally active ADCs (also termed probody-drug conjugates), bispecific ADCs, protein-
degrader ADCs, immune-stimulating ADCs, and dual-drug ADCs, and each of these molecules has unique capabilities to face various challenges (Tsuchikama et al., 2024). As of June 2023, FDA has approved eleven ADCs and available in the market (Gogia et al., 2023). It also assumed that more than 100 ADCs are under clinical trials.
Bispecific Monoclonal Antibodies:
These types of molecules belong to antibodies that recognize two specific targets; two different antigens or two epitopes on the same antigen. Such antibodies offer higher clinical efficacy than monoclonal antibodies, suggesting their role as a potential option for cancer immunotherapy (Cheng et al., 2024). There are some classes of bispecific antibodies available; dual immunomodulators, tumor-targeted immunomodulators, immune effector cell redirectors, and dual tumor-targeting bispecific antibodies (You et al., 2021).
For example, Bispecific T-cell engagers (BiTEs) bind cancer cells and T-cells and provide better efficiency against the cancer cells. BiTE therapy might be effective in a small group of B cell malignancies, including common types of solid cancer. Blinatumomab is first-in-class BiTE approved for the treatment of relapsed and/or refractory B cell-precursor acute lymphoblastic leukaemia (Goebeler and Bargou, 2020).
ROLE OF MONOCLONAL ANTIBODIES IN OTHER THERAPIES
Including therapeutic applications in cancer, monoclonal antibodies are also being used as Antibody-directed enzyme prodrug therapy, Checkpoint therapy, and Immunoliposome therapy, etc (Myhre and Sifris, 2023).
Monoclonal antibodies in the treatment of autoimmune diseases
Monoclonal antibodies play an important role in the treatment of autoimmune diseases. Most of the mAbs-based therapies are developed for oncological and immunological/infectious diseases, but these are being used in the treatment of other diseases (Castelli et al., 2019).
The activation of autoreactive CD4+ T lymphocytes is characterized in autoimmune diseases. Activated T cells lead the production of cytokines and pro-inflammatory molecules, resulting in cell damage and disease progression.
With the increasing understanding of immunological processes in autoimmunity, it is possible to target individual steps of the immune responses, from T cell activation in lymph nodes to T cell differentiation and production of cytokines (Bruno et al., 2011).
Monoclonal antibodies have been developed against many autoimmune diseases such as Ulcerative colitis (a form of IBD), Lupus, Ankylosing spondylitis, Multiple sclerosis (MS), Crohn's disease (a form of IBD), Plaque psoriasis, and Rheumatoid arthritis (RA), etc. (Myhre and Sifris, 2023). For example, FDA has approved two mAbs i.e. Anifrolumab-fnia (Saphnelo), and Belimumab (Benlysta) for the treatment of lupus (Seed, 2024). The monoclonal antibodies against rheumatoid arthritis include mAbs against TNF-a (Infliximab, Adalimumab, Golimumab, Certolizumab, Rituximab), mAbs against (Rituximab), and mAbs interfering with the functions of IL-6 are (Tocilizumab), etc. (Cohen et al., 2013).
Monoclonal antibodies-based therapies are also being approved for the treatment of Covid-19. FDA has approved REGEN-COV (casirivimab and imdevimab administered together)) monoclonal antibody therapy for post-exposure prophylaxis (prevention) for COVID-19 (FDA, 2021).
Monoclonal antibodies in transplantation
Organ transplantation is a life-saving treatment for patients with end-stage organ failure. It is life-saving and increases the quality of life. Organ transplantation requires the use of immunosuppressives to prevent and treat the allograft rejection. But many immunosuppressive agents also cause toxicity and other adverse side effects (Claeys and Vermeire, 2019). The clinical trials of Orthoclone OKT3, and FDA approval in 1985 for use as an antirejection agent for renal transplantation are considered landmarks in the clinical transplantation of solid organs (Smith, 1996). Nowadays wide types of antibodies (monoclonal and polyclonal) are used to prevent and treat solid organ rejections. The cell surface molecules (receptors) associated with rejection are targeted by mAbs to prevent the rejection. For example, OKT3 is an anti-CD3 mAb that disrupts T-cell function
and is used in the treatment of severe rejection episodes (Powelson et al., 1993). Usually, antibodies are also administered to delay the introduction of calcineurin inhibitors, in patients with compromised renal function. Though antibody-based treatments have reduced acute rejection episodes and enhanced graft survival (both short-term and long-term), but opportunistic infections and neoplastic complications may be increased. Thus, it requires proper patient management to balance the risks (Mahmud et al., 2010).
Monoclonal antibodies under research and development
mAbs have wide applications in molecular research in the disciplines of applied biology, immunology, biochemistry, and biotechnology (Ansar et al., 2013). A wide variety of applications of antibodies can be assumed. Interestingly most of these applications of mAbs uses are based on their binding specificity for the target antigen. mAbs are used in the development of therapies, protein purification (affinity-based), diagnostic tools (for example Western blotting, ELISA, Immunohistochemistry, Immunoassays, etc.), diagnostics (use of antibody-containing detection kits, cancer diagnosis, diagnosis of other diseases), detection of cell surface markers, purification of molecules having affinity with antibodies, and elucidation of the structure of cell membrane, etc.
CONCLUSION
Antibodies are immunoglobulins comprising heavy and light chains. Monoclonal antibody-based therapies are playing a key role in the treatment of many diseases including autoimmune diseases, cancers, and infectious diseases. Many mAbs-based therapies are approved by regulatory agencies and many monoclonal antibodies are under clinical trials. Besides, mAbs some other therapies like Antibody-drug conjugates, and bispecific therapies are being investigated for therapeutic purposes. Including therapeutic use, mAbs are also being used in molecular research, disease diagnosis, analysis, and many other applications. Although monoclonal antibodies offer a high order of selectivity and targeted delivery but they have complex structures, undergo modifications, and degradations.
ACKNOWLEDGEMENTS
The authors are thankful to Karaganda Medical University for providing the necessary facilities to conduct this study.
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