Pembrolizumab/Keytruda: Difference between revisions

==Pembrolizumab Antibody Against PD-1 Receptor==

'''Pembrolizumab''', trade name '''Keytruda''', is an immunoglobulin G4 (IgG4)-kappa humanized monoclonal antibody against the programmed cell death-1 (PD-1) receptor. It contains an Fv fragment (PemFv) that is the variable region of the molecule where binding orccurs, as well as a Fab fragment (PemFab) that constitutes the entire molecule. Pembrolizumab is a very compact molecule with an asymmetrical Y-shape. The short compact hinge region inflicts constraints on the molecule that creates the abnormal crystallizable heavy chain/tail region (Fc domain) compared to other immunoglobulin G (IgG) proteins. The heavy chain is <scene name='74/745945/Glycosylation/1'>glycosylated</scene> at both CH₂ domains on each chain and one of them is distinctively rotated 120° compared to other similar structures, making the glycan chain more solvent accessible. IgG4s have a unique function where they form dynamic bispecific antibodies by exchanging half-molecules (one heavy chain/light chain pair) among themselves, called Fab-arm exchange. This makes the molecule particularly unstable and unpredictable as a treatment, but is conquered by introducing the serine-to-proline mutation at <scene name='74/745945/Pro228/1'>amino acid 228</scene>, which prevents Fab-arm exchange and stabilizes the molecule <ref name="log">DOI:10.1080/17425255.2016.1216976</ref>.  

The Fv fragment of Pembrolizumab can form a complex with the extracellular domain (ECD) of PD-1. Both PemFv and PD-1_ECD contain interchain disulfide bonds. PemFv interacts predominantly in the major groove of PD-1, which is formed on one surface by the CC’FG antiparallel β−sheet and the BC, C’D, and FG loops. There are 15 direct hydrogen bonds between the residues, 15 water-mediated hydrogen bonds, 2 salt bridges, and many hydrophobic interactions. There are a total of 26 PD-1_ECD residues involved in the interaction with PemFv, with residues in loop C’D (Pro84 to Gly90) and strand C’ (Gln75 to Lys 78) playing a major role. These key components of PD-1 mainly form interactions through salt bridges and hydrogen bonds with complementary determining regions, the variable domains, of Pembrolizumab. <scene name='74/745945/Chain_b_amino_acids/1'>Thr30, Tyr33, Ser54, Tys101, Arg102</scene> on Chain B of Pembrolizumab form bonds with Asp77, Gln75, Lys78, Thr76, Tyr68, and Asn66 of PD-1. It is believed that the sugar chains of PD-1 have no physical contact with Pembrolizumab due to the N-linked glycosylated residues (Asn49, Asn58, Asn74, and Asn116) being located away from the interface <ref name="horita" />.   

The complex formed when protein-derived ligand, PD-L1, interacts with the inhibitory receptor, PD-1, suppresses immune responses against autoantigens and helps in peripheral immune tolerance. However, when tumors over express PD-L1, the interaction with PD-1 inhibits T-lymphocyte proliferation, release of cytokines, and cytotoxicity, exhausting tumor-specific T-cells. There are a total of 12 PD-1_ECD residues that are involved in forming the complex with the N-terminal half of PD-1_ECD (PD-1_ECD-N). Nine hydrogen bonds, 3 water-mediated hydrogen bonds, 2 salt bridges, and numerous hydrophobic interactions make up the PD-1_ECD/PD-1_ECD-N interaction. The CC’FG sheet within both proteins is the main interaction point. A hydrophobic surface patch is formed when the PD-1_ECD is in complex with PD-L1_ECD-N. The PD-1_ECD residues involved include Val64, Tyr68, Ile126, Leu128, Ala132 and Ile134. Numerous [http://www.nature.com/articles/srep35297/figures/1 Hydrophilic amino acids] that encircle PD-L1_ECD-N form salt bridges and hydrogen bonds with Asn66, Tyr68, Gln75, Thr76, Asp77, Lys78, Ala132 and Glu136 of PD-1_ECD <ref name="horita" />.

T-cells are a major component of the immune response in the human body. They have the ability to recognize cancer-related antigens as non-self and eliminate those cells <ref>doi  10.2147/DDDT.S78036</ref>. PD-L1 and PD-L2 are ligands expressed by some tumors and inhibit T-cell function when bound to PD-1, which is located on the surface of antigen-specific T-cells <ref>doi 10.1007/s40265-016-0543-x</ref>. When PD-L1 is ligated to PD-1 an adaptive immune response occurs, and this allows cancer cells to bypass immune surveillance and grow uncontrollably. Pembrolizumab is an FDA-approved treatment that works as a PD-1 pathway inhibitor to fight numerous forms of cancer, such as metastatic melanoma and non-small cell lung cancer. As an inhibitor, Pembrolizumab targets the cell death of PD-1 and blocks the immune checkpoint pathway. Pembrolizumab has a very high affinity to PD-1, allowing it to block the interaction between PD-1 with PD-L1 and PD-L2 very efficiently. It antagonizes the interaction between PD-1 and its known ligands, and re-activates anti-tumor immunity <ref name="log" />. The PD-1/PD-L1 interaction inhibits T-lymphocyte proliferation, releases cytokines and cytotoxicity, and exhausts tumor-specific T-cells. The inhibition of this pathway reverses the exhausted t-cell phenotype and normalizes the anti-tumor response. One downside of Pembrolizumab is that it may cause inflammatory side effects <ref name="horita" />.