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Rodríguez-Nava, C.; Ortuño-Pineda, C.; Illades-Aguiar, B.; Flores-Alfaro, E.; Leyva-Vázquez, M.A.; Parra-Rojas, I.; Del Moral-Hernández, O.; Vences-Velázquez, A.; Cortés-Sarabia, K.; Alarcón-Romero, L.D.C. Monoclonal Antibodies: Structure and Function. Encyclopedia. Available online: https://encyclopedia.pub/entry/46090 (accessed on 13 September 2024).
Rodríguez-Nava C, Ortuño-Pineda C, Illades-Aguiar B, Flores-Alfaro E, Leyva-Vázquez MA, Parra-Rojas I, et al. Monoclonal Antibodies: Structure and Function. Encyclopedia. Available at: https://encyclopedia.pub/entry/46090. Accessed September 13, 2024.
Rodríguez-Nava, Cynthia, Carlos Ortuño-Pineda, Berenice Illades-Aguiar, Eugenia Flores-Alfaro, Marco Antonio Leyva-Vázquez, Isela Parra-Rojas, Oscar Del Moral-Hernández, Amalia Vences-Velázquez, Karen Cortés-Sarabia, Luz Del Carmen Alarcón-Romero. "Monoclonal Antibodies: Structure and Function" Encyclopedia, https://encyclopedia.pub/entry/46090 (accessed September 13, 2024).
Rodríguez-Nava, C., Ortuño-Pineda, C., Illades-Aguiar, B., Flores-Alfaro, E., Leyva-Vázquez, M.A., Parra-Rojas, I., Del Moral-Hernández, O., Vences-Velázquez, A., Cortés-Sarabia, K., & Alarcón-Romero, L.D.C. (2023, June 27). Monoclonal Antibodies: Structure and Function. In Encyclopedia. https://encyclopedia.pub/entry/46090
Rodríguez-Nava, Cynthia, et al. "Monoclonal Antibodies: Structure and Function." Encyclopedia. Web. 27 June, 2023.
Monoclonal Antibodies: Structure and Function
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This entry is adapted from the peer-reviewed paper 10.3390/biomedicines11061610

Monoclonal antibodies are among the most effective tools for detecting tumor-associated antigens. The U.S. Food and Drug Administration (FDA) has approved more than 36 therapeutic antibodies for developing novel alternative therapies that have significant success rates in fighting cancer. 

: cancer monoclonal antibodies scFv

1. Introduction

Cancer represents one of the leading causes of death worldwide, despite advances in diagnosis and treatment. Several side effects, such as relapse and resistance to therapy, have been associated with the non-specificity of conventional therapies (such as chemotherapy and radiotherapy) [1]. Therefore, the cancer biomedical research community has been focused on searching for specific novel molecules related to each type of cancer for a more personalized therapeutic approach [2]. Antibodies are molecules capable of recognizing tumor cells due to their specific recognition of tumoral antigens. In addition, they can be used to target drugs for immune system activation and early tumor detection [3]. Despite all the promising applications accomplished using monoclonal antibodies (mAb), they also have some therapeutic disadvantages, such as their difficulty in penetrating to solid tumors due to the complexity of the tumor microenvironment. To overcome these difficulties, advances in genetic engineering have enabled the creation of different antibody formats by modifying or eliminating the Fc region. One of the most used is scFv, a novel short format antibody capable of recognizing the target antigen but lacking the fragmented crystallizable (Fc) region. ScFv represents a basic functional unit for developing antibodies and more complex molecules, such as bi-, tri-, tetra-specific, and immunotoxins. However, the small size of these molecules reduces their half-life in blood; therefore, more complex structures are needed to achieve therapeutic effects [4].

2. Cancer Overview

According to the World Health Organization (WHO), in 2019, cancer was the second cause of death in patients younger than 70 years old from 112 countries. In 2020, 19.3 million new cases (18.1 million cases of non-melanoma skin cancer were excluded) and almost 10 million deaths by cancer were reported. About 70% of those deaths were in low- and middle-income countries. In 2040, the number of cases is expected to increase to 28.4 million, representing an increase of 47%. GLOBOCAN reported that the ten most diagnosed types of cancer were: breast (in females) (11.7%), lung (11.4%), colorectal (19%), prostate (7.3%), and stomach (5.6%). However, in terms of mortality, lung cancer (18%), colorectal (9.4%), liver (8.3%), stomach (7.7%), and breast cancer (6.9%) were the most common. If the number of cases was classified according to sex, in men, lung, prostate, and colorectal cancers represent the most frequent, whereas liver and colorectal had the highest mortality rates. In females, breast cancer ranks first in causes of death by cancer, followed by cervical cancer [5].
Cancer is defined as the alteration in the cellular growth of normal cells and can originate in any organ. Tumor cells are characterized by the loss of control of cellular division. According to the WHO, metastasis is typically the actual cause of death due to the multiplication and invasion of adjacent organs by neoplastic cells [6]. Cancer is commonly detected when the number of cells reaches one million or when the tumor size has reached one centimeter, except for in the blood and bone marrow (leukemia and lymphomas), as these do not form solid structures [7]. This process results in the loss of function in normal cells and the gain of malignant characteristics (tumorigenesis) that includes dedifferentiation, increased proliferation, metastasis, apoptosis, and immunosurveillance inhibition, and changes in the metabolism and epigenetic functions (i.e., hallmarks of cancer) [8].
The risk factors for cancer development have been grouped into the following categories: tobacco use; infectious agents; alcohol consumption; ultraviolet or ionizing radiation; obesity; dietary carcinogens; air and water pollution; drugs (diethylstilbestrol and phenacetin); and exposure to occupational carcinogens, along with other risk factors, such as genetics, poor diet, lack of physical activity, poor immune status, and age, which perform an essential role in the development of cancer [9]. However, the WHO stated that many types of cancer have a high chance of being cured if they are diagnosed in the early stages. Due to the worldwide relevance of cancer, the search for alternatives that could improve the diagnosis, treatment, and research has been promoted. Several tools that could identify the target molecules in cancer have been produced, including antibodies that target essential proteins during oncogenic development [10].

3. Monoclonal Antibodies: Structure and Function

Immunoglobulins (Ig) or antibodies have a molecular weight of around 150 kDa and are produced by plasma or B-cells. Structurally, they contain two functional parts: Fc or a crystallizable region (associated with the effector mechanism) and a fragmented antigen-binding (Fab) region for the recognition of the target antigen. The two functional regions of the antibody are composed of two polypeptide chains: two light and two heavy chains, joined by disulfide bonds that confer stability and rigidity. The heavy chains have one variable domain (VH) and three constant domains (CH1, CH2, and CH3). The light chain has one variable domain (VL) and one constant domain (CL). The Fab region is made up of VH and CH1 together with VL and CL, while the Fc region consists of two segments, CH2 and CH3. Antibodies also have post-translational modifications, such as glycosylation in the Fc domain, that stabilize and modulate the binding to Fc receptors [11].

3.1. Monoclonal Antibodies Production Methods

Monoclonal antibodies (mAbs) come from a single cellular clone that has been divided multiple times in order to produce antibodies against the same antigen. The most common antibody production method is based on the generation of hybridomas, which are cells derived from the fusion of spleen and myeloma cells. Hybridomas possess two fundamental abilities: produce antibodies and proliferate indefinitely [12]. The method consists of immunizing mice with the antigen, spleen extraction, and fusion with myeloma cells. Hybrids are cloned by limiting dilution to ensure the growth and proliferation of one single cell per well. Finally, the clone is expanded, and the antibody is purified from the culture medium and validated [13]. The generation of hybridomas has been the most common technique for mAb production, and this technique can be modified or changed for the specific production of therapeutic antibodies. The substitution of murine regions with human sequences and the preservation of the Fab region has resulted in chimeric antibodies (-ximab), while the substitution of the Fc and Fab domains with human sequences and the preservation of the murine hypervariable regions (CDR) has resulted in antibodies that are close to the human version. Finally, the production of fully human antibodies (-zumab) has been achieved by using transgenic mice and molecular biology techniques [14].
For the generation of chimeric, humanized, and fully human antibodies, different genetic engineering techniques have been developed. These techniques have been based on the use of transgenic animals and the amplification of genes that encode for the antibody from B-cells or hybridomas. The process began starts with RNA extraction, cDNA synthesis by reverse transcription, then the subsequent amplification of the heavy and light chain encoding genes by PCR. Afterward, genes were cloned into different expression systems, such as bacteria, yeasts, and mammal cells. At this point, several formats could be obtained using specific regions derived from the antibody to facilitate large-scale production for commercial and therapeutic purposes [15][16][17].

3.2. Monoclonal Antibodies in Cancer Treatment

The use of monoclonal antibodies has been considered a novel treatment against cancer in conjunction with conventional therapies, such as surgery, radiation, and chemotherapy. The main advantages of mAbs are their mechanism of action, which could promote the death of tumor cells by recognizing the tumor-associated antigens (TAA) and the stimulation of long-lasting antitumoral activities without any effect on healthy cells [14]. TAA are proteins overexpressed on the surface of tumor cells, including mutated proteins and those with post-translational modifications [18][19].
Since the approval of the first commercial monoclonal antibody (Rituximab) by the U.S. FDA in 1997, many antibodies have been developed and approved [20]. Rituximab is a chimeric antibody that targets the loops H1, H2, H3, and L3 (169-PANPSE-174 and 183-CYSIQ-187 regions) of the extracellular domain of CD20 [21][22]. CD20 is expressed in B-cell during maturation and B-cell neoplastic cells, and it is lost after differentiation to plasmatic cells. Due to the success of Rituximab in the treatment of non-Hodgkin’s lymphoma, other antibodies targeting CD20 were developed [23]. Additional research enabled the authorization of mAbs for more than one type of cancer; for example, Sacituzumab Govitecan was approved for the first time in 2020 for the treatment of solid tumors. Furthermore, it was recently approved for use in patients with metastatic or locally advanced urothelial cancer [24], triple-negative breast cancer [25], and HR-positive breast cancer [26]. In addition, it was proposed the combinations of various mAbs targeting different TAAs [27]. MAbs are biological reagents that can be modified, improved, and continuously evolved to enhance their efficacy in multiple types of cancer.
Therapeutic mAbs approved by the FDA target a special type of TAA, named differentiation clusters, which are overexpressed on the surface of lymphocytes (used in directed therapies against hematopoietic tumors), growth factors essential for the cellular proliferation in specific tissues (targets in the treatment of solid tumors) and transmembrane proteins involved in cellular adhesion (Nectin 4), signaling transduction (Trop2) and immunological checkpoints (PD-1/PD-L1). Based on the current successful antibodies and therapeutic targets, novel antibodies targeting different epitopes were developed. For example, Cetuximab, Necitumumab, and Panitumumab target the same TAA but different epitopes in domain III of EGFR, and they compete with EGF for the binding site in EGFR to block signaling and cellular proliferation. Panitumumab overlapped with the binding site of EGF in D355 and K443, whereas Cetuximab overlapped with the binding site in D355, Q408, H409, K433, and S468 [28]. However, due to the presence of structural mutations in the sequence of domain III in EGFR, a notable decrease in the recognition of these antibodies was observed [29]. The main reported mutations described in EGFR were the following: V441, S442, I462, S464L, G465R, I491M, K467T, K489, and S492R. These could be involved in the resistance to therapy due to their presence in epitopes recognized by Panitumumab and Cetuximab [30][31][32]. It was reported that Necitumumab could bind to EGFR, in addition to the mutation S492R, in the domain III of EGFR that conferred resistance to Cetuximab [33]. Additional studies were performed to analyze the presence of novel epitopes in the same domain to target novel antibodies and provide new alternatives in the case of resistance [34].
In addition to the homology of the target, all the aforementioned antibodies possess unique structural and functional characteristics. For example, among anti-EGFR, Cetuximab is an IgG1 mAb, and Panitumumab is an IgG2, and the structural difference was the size of the hinge (15 amino acids for IgG1 and 12 to IgG2) that was associated with flexibility [35]. It was reported that Cetuximab was capable of inducing the activation of cytotoxic T cells against tumor cells, while Panitumumab had a low binding affinity to CD16 and could not induce ADCC promoted by NK cells or cytotoxic T cells; however, it could induce cytotoxicity mediated by neutrophils and monocytes [28].

3.2.1. Effector Mechanisms of mAb in Therapy

In mammals, antibodies have been classified into five classes: IgM, IgD, IgG, IgE, and IgA. The most commonly used isotype in cancer therapy is IgG [36]. The characteristic “Y” shape of antibodies has been associated with the basic unit of Ig. Antibodies can specifically recognize one defined antigen in Fab regions and perform its biological functions in the Fc region, which could then bind to cellular receptors in macrophages or mast cells or mediate cytotoxic activities by the complement or NK cells [37].

Blocking Signaling Pathways

MAbs can induce the death of tumor cells by blocking the signaling pathways associated with growth factor receptorsGrowth signaling and tumor survival could be interrupted when a mAb recognize by the Fab region to receptors for the growth factors and inactivates signaling pathways or blocks the of the ligand. For example, one of the most used targets with this mechanism was the receptor for the epidermal growth factor (EGFR) [38], which can be overexpressed in different types of cancer, such as colon, neck, and head, ovary, and lung, among others. It was reported that the activation of EGFR promoted an increase in the proliferation rate, migration, and cellular invasion, through the stimulation of the signaling pathways phosphoinositol 3-kinase (PI3K) and guanosine triphosphatase (GTPase) Ras [39].
Some mAbs approved by the FDA act by blocking signaling pathways, such as Cetuximab and Panitumumab. Cetuximab was able to bind to EGFR and competitively inhibited the binding to the epidermal growth factor (EGF) and other ligands, which blocked the phosphorylation of EGFR induced by ligands and mitigated the activation of the signaling pathways related to cancer development [40]. Panitumumab is an antagonist and induces the internalization of EGFR. The intracellular processes triggered by EGFR activation (e.g., dimerization, autophosphorylation, and signal transduction) were prevented using this mAb, which promoted an increase in the apoptotic rate and a reduction in the proliferation and angiogenesis of tumor cells [41].

Antibody-Dependent Cellular Cytotoxicity

Antibody-dependent cellular cytotoxicity (ADCC) is an effector function derived from the antibody binding to the tumor cell and immune cells. The variable regions of the antibody could bind to antigens in the tumor cell, and the Fc region could bind to the Fcγ receptors (FcγR) expressed in leukocytes; for example, FcγRIIIA expressed in natural killer (NK) cells promoted cellular destruction through the release of lytic factors [42]. Tafasitamab is one of the most recently approved therapeutic mAbs by the FDA; its target is CD19, a differentiation cluster successfully used as a target for other therapeutic antibodies, such as Loncastuximab and Blinatumomab. The expression of CD19 is limited to B-cells during maturation and is overexpressed in B-cell-associated tumors [43]. Tafasitamab contains modifications in the Fc (two amino acid substitutions: S239D and I332E) to increase the binding to Fcγ and improve the ADCC. This modification increased not only the ADCC activity but also promoted the induction of antibody-dependent cellular phagocytosis (ADCP) [44].

Antibody-Dependent Cellular Phagocytosis

ADCP is the biological function mediated by the binding of Fc with the FcγRI receptor expressed in macrophages, neutrophils, and eosinophils. ADCP is the mechanism by which the antibodies opsonize the tumor cell for its internalization and degradation in the phagosome. In general, it has been observed that antibodies that induced ADCC (for example, Tafasitamab) could promote ADCP, which was associated with the production of gamma-interferon (IFN-γ) by NK cells that induced the expression of the FcγRI in polymorphonuclear cells, thus, promoting phagocytosis [45]. Daratumumab was the first fully human IgG1-κ against the C-terminal loop in the residues 189–202 and 223–236 of CD38. This antibody was approved for the treatment of multiple myeloma, and it is expressed at low levels in normal lymphoid cells, myeloid cells, and some non-hematopoietic tissues. Daratumumab could promote several effector mechanisms in myeloma cells, such as ADCC, ADCP, complement-dependent cytotoxicity (CDC), apoptosis, and the modulation of CD38 enzyme activities [46].

Complement-Dependent Cytotoxicity

Many therapeutic mAbs used in the conventional treatment against cancer can promote the activation of the complement classical pathway (CDC), specifically those with the IgG1 isotype. IgG1 antibodies can simultaneously promote the activation of receptors in macrophages and NK cells (Fcγ); at the same time, they regulate CDC, to which most of the therapeutic mAb try to preserve the Fc region of the IgG1. The mAbs were able to bind to the tumoral antigens expressed in the membrane of the target cell; thereafter, C1q was able to bind to the Fc region of the antibody for the activation of the proteolytic process, which then enabled the binding of other complement factors until poly-C9 was attached to the target cell for the formation of the membrane-attack-complex (MAC) [47].
As an example, Rituximab could promote synergy between ADCC (mediated by NK cells), ADCP (mediated by macrophages), and CDC [48]. Other antibodies, such as Naxitamab, also promoted this mechanism. The target molecule of Naxitamab was the glycolipid GD2, a disialoganglioside overexpressed in neuroblastoma and other neuroectodermal cells, including the central nervous system and peripheral nerves. During in vitro studies, Naxitamab was able to bind to GD2 at the cellular surface and induced CDC and ADCC [49] (Figure 1D).

3.2.2. Conjugated Antibodies

Another fascinating application of mAbs has been their use as vehicles in the transport of drugs due to their specificity and high affinity. The use of antibody-drug conjugates (ADC) arose from the need to enhance the antitumoral effects of conventional treatments, taking advantage of their specificity to target antigens in order to increase the antitumoral activity. During ADC, different effector molecules (cytotoxic agents, toxins from bacteria, proteins, plants, and radiopharmaceutical agents) promoted cellular death after binding to and internalizing antibodies [50].
Tisotumab vedotin-tftv has been a successful ADC against the tissue factor (TF) (coagulation pathway), which performs an essential role as a receptor in signaling pathways related to cancer development. This ADC is a human IgG1 conjugated to a small molecule of monomethyl auristatin E (MMAE), a disruptor agent of microtubules. The effector mechanism of Tisotumab vedotin-tftv was the binding of the antibody to TF expressed in the tumor cells, the internalization of the ADC-TF, and the release of the MMAE by proteolytic cleavage. Later, MMAE disrupts the microtubule network in the actively dividing cells, which stops the cell cycle and induce cellular death by apoptosis. Additionally, Tisotumab vedotin-tftv can promote ADCP and ADCC by the Fc region of the antibody [51].

3.2.3. Disadvantages of mAb-Based Therapy

Unfortunately, only some of the mAbs have been as successful as Rituximab and other therapeutic mAbs approved by the FDA. One of the major inconveniences in therapeutic mAbs is the development of drug resistance, which increases the need to improve the knowledge of their mechanisms of action. Modifications could overcome this resistance in the conjugation with other compounds, changes in the Fc region to enhance NK cells and macrophages activation, or their use as support during conventional therapy [52][53].
On the other hand, mAbs are multimeric proteins with a molecular weight of 150 kDa, and they contain disulfide bonds and N-linked glycans as posttranslational modifications. In addition, for their in vitro production, they require sophisticated eukaryotic machinery, which increases the concentration of the antibody required during the treatment, making them inaccessible to all the patients. For this purpose, several strategies have been developed for cost reduction in commercial antibodies, such as Rituximab [54]. Historically, the first therapeutic mAbs derived from mice resulted in side effects, such as immunogenicity and poor immune response, limiting their clinical use. Currently, this disadvantage has been circumvented using biotechnological techniques that enabled the translation of the murine Fc into a fully human Fc or the complete deletion of this region for the generation of other formats of antibodies [55].

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Subjects: Biochemistry & Molecular Biology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Cynthia Rodríguez-Nava
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Carlos Ortuño-Pineda
,
Berenice Illades-Aguiar
,
Eugenia Flores-Alfaro
,
Marco Antonio Leyva-Vázquez
,
Isela Parra-Rojas
,
Oscar del Moral-Hernández
,
Amalia Vences-Velázquez
,
Karen Cortés-Sarabia
,
Luz del Carmen Alarcón-Romero
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Revisions: 2 times (View History)
Update Date: 29 Jun 2023
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