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Nivolumab

Nivolumab that is also called as MDX 1106, BMS 936558, ONO 4538 and OPDIVO; it is a compound that is produced in the laboratory by exploiting the genetic engineering technology. Chemically, it is globin protein that either enhances the performance or supports immune system; thus, it is regarded as an antibody or otherwise immunoglobulin. Nivolumab follows the generalized structure of an immunoglobulin; that is shown in Figure 1. More specifically, it belongs to the Immunoglobulin G4 (IgG4) subclass of the class Immunoglobulin G (IgG). It can specifically bind to its ligand that is programmed death-1 (PD-1) receptor protein with a high affinity and forms a molecular complex; because its nature of being monoclonal. The crystal structure of this molecular complex is diagrammatically presented in Figure 2. while the surface representation of this molecular complex is diagrammatically presented in Figure 3.  This molecular complex is primarily stabilized by the hydrogen bonding and Van der Waals forces. Moreover, it is fully human antibody which makes it compatible with the immune system of the human body. In simple words, the immune system of the human body does not evoke an immune response against it when it is encountered.

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Figure 1 Nivolumab Structure: Structure of a Generalized Immunoglobulin/ Antibody

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Figure 2 The Crystal structure of the Molecular Complex between programmed death-1 (PD-1) receptor protein which is shown in green and the Fab region (fragment antigen-binding region) of the Nivolumab, is represented using the ribbon representation. For the Nivolumab, the heavy chains are shown in orange; while the light chains are shown in purple. Only Fab region of the Nivolumab is shown here, the part of the Nivolumab which interacts with its target

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Figure 3 The Surface Representation of the Molecular Complex between programmed death-1 (PD-1) receptor protein and the Nivolumab. Here, the surface of PD-1 in PD-1/ Nivolumab is shown in green; on the other hand, the epitope regions for the heavy and light chains of nivolumab are shown in orange and red, respectively

As stated earlier, an antibody/ immunoglobulin interacts with the immune system in a positive manner. Similarly, Nivolumab interacts, binds and activates an immune checkpoint molecule, that is a receptor protein more specifically immunoreceptor namely programmed death-1 (PD-1) which is a transmembrane protein of TYPE 1 characterized by the presence of only one extracellular Ig variable (V) domain. Thereby, it also prevents its interaction with its legitimate ligands namely PD-L1 and PD-L2; in this way, the inhibition of the programmed death-1 (PD-1) receptor protein by its ligands is prevented. The structure of the molecular complexes they form with the programmed death-1 (PD-1) is shown in Figure 4 and Figure 5 In other words, Nivolumab works as an Anti-PD-1 Antibody. The programmed death-1 (PD-1) receptor protein is expressed on a number of cells, for example, CD 4 lymphocytes, CD8 lymphocytes, B lymphocytes, Natural Killer Cells, T regulatory Cells, etc. we can say that Nivolumab can potentially inhibit the abnormal functions of all those cells which are mentioned above, and more importantly all of these are immune system cells of the immune system.  Thus, Nivolumab can potentially support the normal functionalities of a major part of the immune system.

Both PD-L1 and PD-L2 are also expressed on the surface of the plasma membrane or/ in the cytoplasm of different cells, for example, PD-L1 expresses on macrophages, CD274, T cells, B cells, B7-H1 and dendritic cells; while, on the other hand, PD-L2 is expressed on the CD273, macrophages, B7-DC and dendritic cells. Under normal physiological condition, both PD-L1 and PD-L2 generates an appropriately weak level of inhibitory signal upon binding to the programmed death-1 (PD-1) receptor protein. The crystal representation of PD-1/ PD-L1 is diagrammatically shown in Figure 4. This weak inhibitory signal negatively controls the cell proliferation of the T cell as well as the cytokines production in them, which is a normal controlling mechanism. Thus, a normal level of T cells population is formed that leads the tumor cells expressing specific antigen to the apoptosis, a type of programmed cell death. While, on the other hand, under abnormal neoplastic condition, both abnormally upregulated PD-L1 and PD-L2 generate a very strong inhibitory signal upon binding to the programmed death-1 (PD-1) receptor protein. As a result, T cell cannot proliferate enough and their number drops as well as the cytokine production is also very much decreased; this was all the immune responses of T cells are suppressed. The expression of PD-L1 and PD-L2 is upregulated via the interleukin 4 (IL4), interleukin 10 (IL10) and interferons (alpha, beta and gamma). As a result, the effector function that is the release of effector proteins, is downregulated in the T cells.

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Figure 4 The Surface Representation of the Molecular Complex between programmed death-1 (PD-1) receptor protein and its ligand PD-L1. Here, the surface of PD-1 in PD-1/ PD-L1 complex is shown in light blue; on the other hand, binding site for the PD-L1 on the surface of PD-1 is shown in bright blue

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Figure 5 The Ribbon Representation of the Molecular Complex between programmed death-1 (PD-1) receptor protein (only the extracellular domain IgV is shown in green with red labels) and its ligand PD-L2. Here, the PD-L2 is shown in cyan with blue labels

Under normal physiological condition, the programmed death-1 (PD-1) receptor protein prevents the human body from the initiation of inflammation and autoimmunity as it is expressed by a broad range of immune cells. On the other hand, under abnormal neoplastic condition, the normal functionalities of the same programmed death-1 (PD-1) receptor protein become highly suppressed. This suppression is caused by progression of programmed death-1 / programmed death-1 ligand (PD-1/ PD-L1) signalling pathway that is a cell-to-cell signalling pathway. This complex signalling is diagrammatically presented in a simplified form in Figure 6 this PD-1/ PD-L1 signalling pathway is inhibited via the Nivolumab treatment. By this, the T cell can proliferate as well as generate cytokines as a normal rate and thus contribute again to the immunity. This is also highlighted in red.

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Figure 6 The programmed death-1 / programmed death-1 ligand (PD-1/ PD-L1) Signaling Pathway is a cell-to-cell signalling pathway as both the ligands PD-L1 and PD-L2 as well as the receptor protein PD-1 are expressed on different cell type; and, the thereby mediated signaling is a complex cell-to-cell signalling. In addition, the Nivolumab mediated blocking of PD-1/ PD-L1 signalling pathway is also highlighted in red

Clinically, Nivolumab is a pharmaceutical drug that is approved by U. S. Food and Drug Administration FDA for the treatment of a broad spectrum of neoplasms/ cancers, for example, Non-Small Cells Lung Cancer, Renal Cell Carcinoma, unresectable melanoma, Hodgkin lymphoma, squamous head and neck cancer, urothelial carcinoma, and as a second treatment option for liver cancer.



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