Sandbox 9888: Difference between revisions

Remicade (Infliximab) is a chimeric IgG1 monoclonal antibody consisting of 597 amino acids, weighing 149,000 Daltons <ref>PMID:23504311</ref>. This chimeric monoclonal antibody is produced when the variable regions of a murine antibody (25%)  is fused with the constant regions of a human antibody (75%) at the hinge region through a genetic engineering process<ref>PMID:17592358</ref>. Within the hinge region, intramolecular disulfide bonds stabilize the two fragment antigen binding regions (Fab) to the fragment crystallizable region (Fc). <scene name='74/744162/Variable_chains_hc/1'>Click here to view separated Fab and Fc regions</scene>. The Fab regions are comprised of both a heavy and light chain, while the Fc region consist of only a heavy chain. Located in the folded Vh and Ch domains of the heavy chain, amino acid residues Glu-1 to Thr-226 are found <ref>PMID:23504311</ref>. <scene name='74/744162/Heavy_chain/1'>The heavy chain region is highlighted here, and only (1 of 3) molecules are shown, for simplicity</scene>. In addition, the <scene name='74/744162/Light_chain/1'>light chain</scene> is composed of residues Asp-1 to Cys-214 that fold into the Vl and Cl domain <ref>PMID:23504311</ref>. The heavy and light chain at the N-terminus form the variable region that functions as a receptor binding site.

After intravenously injecting Infliximab, the p55 and p75 receptors (TNF-R?) on TNF-α are neutralized when bound to the drugs high affinity receptor binding sites <ref>PMID:17916444</ref>. The complex formed is stabilized through the vast array of weak interactions between the two proteins, such as hydrogen bonds, salt bridges, and Van der Waal forces <ref>PMID:23504311</ref>. Specifically, TNF-α contributes to the stability by creating a <scene name='74/744162/Hydrophobic_interface/1'>hydrophobic interface</scene> <ref>PMID:2777790</ref> through amino acid residues such as the <scene name='74/744162/Tyr_141_atom/3'>Tyr-141 side chain</scene> <ref>PMID:23504311</ref>. This interface is formed primarily by the C-D and E-F <scene name='74/744162/Loops_tnf/2'>loop residues</scene> connecting the antiparallel 8-stranded Beta sheets <ref>PMID:23504311</ref>. To view the loop residues of the full structure complex, <scene name='74/744162/Loops_tnf_3molecule/1'>click here</scene>. These favorable interactions are essential to the complex formed between TNF-α and infliximab Fab.

In determining the proper amount of how much of the drug should be injected, Remicade is able to sufficiently block TNF-α from interacting with the TNF receptors (TNFR) <ref>PMID:17916444</ref>. Thus, inhibiting the receptor from signaling production of IL-1 and IL-6, both of which are pro-inflammatory cytokines <ref>PMID:27100432</ref>. When this occurs, Remicade acts as a competitive inhibitor to TNF-R. If an adequate amount is introduced, the interface will be obstructed, thus preventing TNF-α from participating further in diseases.  

Once the complex forms, it is stabilized by the amino acid residues <scene name='74/744162/Cdef_residues/1'>Gln67–His73 and Gln102–Lys112</scene> of the C-D and E-F loops <ref>PMID:23504311</ref>. Particularly, the weak interactions between the loops and side chains, allows for a stronger binding affinity. (ASK ABOUT ACIDIC CHAIN SUBSTITUTIONS) The strongest interaction between the two proteins is best seen in the peak region of TNF. This arises when TNF-α is in its active form and exists as a trimer <ref>PMID:23504311</ref>. Although, research has offered some insight into the mechanisms of how Remicade effectively inhibits TNF-α, studies have not shown a clear understanding of the extensive underlying network. Thus, more research into this matter should be pursued.

Plaque psoriasis is the most common form of the disease, appearing as raised, red patches covered with a off-white buildup of dead skin cells <ref>PMID:19537380</ref>. These plaques typically appear on the scalp, knees, elbows and lower back <ref>PMID:19537380</ref>. Remicade has been FDA approved for the treatment of adult patients expressing severe, chronic symptoms <ref>PMID:19537380</ref>. The severity of the disease is ultimately assessed by a physician to determine if Remicade is the right course of action in consideration with other possible therapies <ref>PMID:19537380</ref>.