Ofatumumab: Difference between revisions

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New page: <applet load="" size="480" color="" frame="true" spin="on" Scene ="" align="right" caption="Ofatumumab, better known as Arzerra, (3giz)"/> ===Better Known as: Arzerra=== * Marketed ...
 
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<applet  load="" size="480" color="" frame="true"  spin="on" Scene ="" align="right" caption="Ofatumumab, better known as Arzerra, ([[3giz]])"/>
<StructureSection load='3giz' size='450' side='right' scene='Ofatumumab/Ofatumumab/1' caption='Ofatumumab Fab Fragment, better known as Arzerra, ([[3giz]])'>
__TOC__
===Better Known as: Arzerra===
===Better Known as: Arzerra===
* Marketed By: GlaxoSmithKline
* Marketed By: Genmab & GlaxoSmithKline
* Major Indication: Chronic Lymphocytic [[Cancer|Leukemia]]
* Major Indications: Chronic Lymphocytic [[Cancer|Leukemia]] & [[Rheumatoid Arthritis]]
* Drug Class: Anti-CD20 [[Monoclonal Antibody]]
* Drug Class: Anti-CD20 [[Monoclonal Antibody]]
* Date of FDA Approval: 1999 (2016)
* Date of FDA Approval (Patent Expiration): 2009 (2023)
* 2009 Sales: $3.1 Billion
* 2010 Sales: $60 Million
* Importance: It has been proposed that the closer the inhibitor resembles the natural substrate ([[Sialic acid]]), the less likely they are to select drug-resistant mutant viruses. It was along this train of thought that Oseltamivir was designed. It was approved by the FDA just a few months after [[Zanamivir]] and quickly garnered 75% of the influenza market share. Many newer strains of [[Influenza]], namely [User:Michael Strong/H1N1|H1N1]] have become resistant to Oseltamivir however, shifting market share back toward Zanamivir for which influenza has remained relatively unresistant toward.  
* Importance: Recieved accelerated approval by the FDA for treatment of Chronic Lymphocytic [[Cancer|Leukemia]]. Targets a different CD20 epitope than [[Rituximab]]. This epitope is located closer to the cell membrane, which should allow for more effective complement deposition and subsequent cancerous B-Cell killing. Numerous studies validated this increased cytotoxicity. Further, Ofatumumab dissociates from its target at a slower rate compared to Rituximab. Currently being tested for efficacy in a number of phase II and III trials for B-Cell Lymphoma and Rheumatoid Arthritis as well as Multiple Sclerosis.<ref>PMID 18003886</ref><ref>PMID: 20068404</ref>
* See [[Pharmaceutical Drugs]] for more information about other drugs and diseases.
* See [[Pharmaceutical Drugs]] for more information about other drugs and diseases.


===Mechanism of Action===
===Mechanism of Action===
Viral [[Neuraminidase]] is one of two major glycoproteins found on the surface of [[influenza]] viral membranes, the other being [[hemagglutinin]]. When the influenza virus infects a host cell, it attaches itself to the host via hemagglutinin interactions with host glycans, facilitating the fusion of host endosomal membrane with the viral membrane. After the virus has successfully infected the host and replicated extensively, the viral cargo is released from the cell via budding. During the budding process, the viral cargo is attached to the host cell once again via hemagglutinins, allowing the viral particle to form completely. Once the viral particle is formed, Neuraminidase cleaves the terminal sialic (neuraminic) acid residues from the glycan structures on the surface of the infected cell, breaking the hemmaglutinin-glycan interaction and promoting release of the viral particle to infect other cells. Oseltamivir is a prodrug which is rapidly metabolized into its active form. It functions by inhibiting the function of <scene name='Oseltamivir/N1_neuraminidase/1'>viral neuraminidase</scene>, preventing the viral particle from being released from the infected cell, thus limiting the severity and spread of [[viral infections]].<ref>PMID:1438172</ref> It binds to the active site of Neuraminidase causing dramatic conformational adjustments which render the protein non-functional. This prevents neuraminidase from cleaving the hemmaglutinin-glycan tethers and releasing the viral cargo after viral replication. Oseltamivir binding causes the <scene name='Oseltamivir/150_loops/1'>so-called 150 loop</scene> (residues 147-151) to shift, <scene name='Oseltamivir/Actve/2'>covering part of the binding pocket</scene>, while Oseltamivir situates itself <scene name='Oseltamivir/Os_ac/1'>firmly within the active site</scene> using hydrogen bonds to residues Tyr 406, Arg 371, and Arg 152 along with a number of <scene name='Oseltamivir/Bound/1'>other interactions</scene>. Of note, the <scene name='Oseltamivir/His/1'>well known mutation</scene> of His 274 to Tyr confers resistance to Oseltamivir because the interaction between Tyr 274 & Glu 276, <scene name='Oseltamivir/His/2'>shifts Glu 276 into the binding site</scene> of Oseltamivir, increasing the K<sub>i</sub> of Oseltamivir 265 fold. This is not the case with [[Zanamivir]], which is barely impacted by the H274Y mutation (K<sub>i</sub> increases by only 2 fold).<ref>PMID: 18480754</ref>
Chronic Lymphocytic [[Cancer|Leukemia]] & [[Rheumatoid Arthritis]] are diseases associated with B-cell dysfunction. B-cells play a key role in the humoral immune system by acting as antigen-presenting cells (which activate T-cells) and by eventually producing antibodies against invading antigens.<ref>doi:10.1016/j.it.2006.07.005</ref> Although the function of B-Lymphocyte Antigen CD20 has not yet been determined, and in fact knockout mice which do not produce CD20 are healthy, CD20 is expressed on almost all normal and malignant B-cells.<ref>PMID: 15564720</ref> A number of studies have demonstrated that the binding of [[monoclonal antibodies]] to CD20 results in recruitment of immunological devices that trigger cytotoxic events, such as compliment-dependent cytotoxicity (CDC). CDC is the major natural immune response in the body triggered by [[antibody]] binding, used to eliminate invading or dysfunctional pathogenic cells.<ref>PMID 20068404</ref> Ofatumumab is an anti-CD20 human monoclonal antibody which binds a unique epitope on CD20 with high specificity. This epitope is membrane proximal compared to the epitope of [[Rituximab]], which might explain Ofatumumab's increased potency compared to that of Rituximab. Further, because the epitope of Ofatumumab includes a small extracellular loop of CD20 and binds very tightly resulting in a slow off-rate, this too may explain Ofatumumab's increased CDC potency.<ref>PMID:16785532</ref>
 
</StructureSection>
===Pharmacokinetics===
<table style="background: cellspacing="0px"  align="" cellpadding="0px" width="52%">
<tr>
<td style="width:100%; vertical-align:top;border-width:0px; border-style:inset">
<div style="height:100%; width: 100%">
{{:Neuraminidase Inhibitor Pharmacokinetics}}
</div>
</td>
</tr>
</table>
 
===References===
===References===
<references/>
<references/>
__NOEDITSECTION__
__NOEDITSECTION__
__NOTOC__

Latest revision as of 19:01, 16 January 2017

Better Known as: Arzerra

  • Marketed By: Genmab & GlaxoSmithKline
  • Major Indications: Chronic Lymphocytic Leukemia & Rheumatoid Arthritis
  • Drug Class: Anti-CD20 Monoclonal Antibody
  • Date of FDA Approval (Patent Expiration): 2009 (2023)
  • 2010 Sales: $60 Million
  • Importance: Recieved accelerated approval by the FDA for treatment of Chronic Lymphocytic Leukemia. Targets a different CD20 epitope than Rituximab. This epitope is located closer to the cell membrane, which should allow for more effective complement deposition and subsequent cancerous B-Cell killing. Numerous studies validated this increased cytotoxicity. Further, Ofatumumab dissociates from its target at a slower rate compared to Rituximab. Currently being tested for efficacy in a number of phase II and III trials for B-Cell Lymphoma and Rheumatoid Arthritis as well as Multiple Sclerosis.[1][2]
  • See Pharmaceutical Drugs for more information about other drugs and diseases.

Mechanism of Action

Chronic Lymphocytic Leukemia & Rheumatoid Arthritis are diseases associated with B-cell dysfunction. B-cells play a key role in the humoral immune system by acting as antigen-presenting cells (which activate T-cells) and by eventually producing antibodies against invading antigens.[3] Although the function of B-Lymphocyte Antigen CD20 has not yet been determined, and in fact knockout mice which do not produce CD20 are healthy, CD20 is expressed on almost all normal and malignant B-cells.[4] A number of studies have demonstrated that the binding of monoclonal antibodies to CD20 results in recruitment of immunological devices that trigger cytotoxic events, such as compliment-dependent cytotoxicity (CDC). CDC is the major natural immune response in the body triggered by antibody binding, used to eliminate invading or dysfunctional pathogenic cells.[5] Ofatumumab is an anti-CD20 human monoclonal antibody which binds a unique epitope on CD20 with high specificity. This epitope is membrane proximal compared to the epitope of Rituximab, which might explain Ofatumumab's increased potency compared to that of Rituximab. Further, because the epitope of Ofatumumab includes a small extracellular loop of CD20 and binds very tightly resulting in a slow off-rate, this too may explain Ofatumumab's increased CDC potency.[6]

Ofatumumab Fab Fragment, better known as Arzerra, (3giz)

Drag the structure with the mouse to rotate

References

  1. ↑ Coiffier B, Lepretre S, Pedersen LM, Gadeberg O, Fredriksen H, van Oers MH, Wooldridge J, Kloczko J, Holowiecki J, Hellmann A, Walewski J, Flensburg M, Petersen J, Robak T. Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1-2 study. Blood. 2008 Feb 1;111(3):1094-100. Epub 2007 Nov 14. PMID:18003886 doi:10.1182/blood-2007-09-111781
  2. ↑ Zhang B. Ofatumumab. MAbs. 2009 Jul-Aug;1(4):326-31. Epub 2009 Jul 1. PMID:20068404
  3. ↑ Montecino-Rodriguez E, Dorshkind K. New perspectives in B-1 B cell development and function. Trends Immunol. 2006 Sep;27(9):428-33. Epub 2006 Jul 24. PMID:16861037 doi:10.1016/j.it.2006.07.005
  4. ↑ Cragg MS, Walshe CA, Ivanov AO, Glennie MJ. The biology of CD20 and its potential as a target for mAb therapy. Curr Dir Autoimmun. 2005;8:140-74. PMID:15564720 doi:10.1159/000082102
  5. ↑ Zhang B. Ofatumumab. MAbs. 2009 Jul-Aug;1(4):326-31. Epub 2009 Jul 1. PMID:20068404
  6. ↑ Teeling JL, Mackus WJ, Wiegman LJ, van den Brakel JH, Beers SA, French RR, van Meerten T, Ebeling S, Vink T, Slootstra JW, Parren PW, Glennie MJ, van de Winkel JG. The biological activity of human CD20 monoclonal antibodies is linked to unique epitopes on CD20. J Immunol. 2006 Jul 1;177(1):362-71. PMID:16785532

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