PP6011 TNF And Rheumatoid Arthritis: Drug Target Validation Case Study Assessment Answer

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Question :

PP6011 Drug Target Validation Case Study. Term 1, 2019

Maximum 1000 words excluding references, tables, and figure legends.

In this component, learners will present the evidence for the proof of concept and validation of a drug target for a biologic. In this case this will be infliximab, the pathfinding biologic that has revolutionised the treatment of rheumatoid arthritis. 

This is based on a lecture and problem based learning session that has discussed the process toward the discovery of TNF as a molecule of major importance, and proof that its inhibition may be of benefit to rheumatoid arthritis patients, to the first clinical trial, and then the phase-II trial that finally proved the clinical efficacy.

The learner should structure this according to the priorities they feel are important to the progress and success of the biologic, with headings.

The study should be well presented, fit for showing to a future employer. It will be uploaded onto Turnitin.

The Study should:

  • Relate the progress of ideas as they occurred.
  • Present evidence from original and contemporaneous scientific papers with only essential reference to reviews and no reference to textbooks. 
  • Use the Cite it Right referencing format. Using Endnote would be recommended.
  • Cover the discovery of TNF as a target relating to the classical stages of preclinical validation of a drug target, namely:
    • Is the target up-regulated in the appropriate disease state?
    • Is spatial and temporal expression consistent with the proposed role in the disease pathology?
    • Does removal or inhibition of the target ameliorate signs for which it is thought to be responsible?
    • Does increasing the activity of the target exacerbate signs for which it is thought responsible?
    • The report should not use these as titles or headings. Sections should be created according to the message the writer wishes to convey. 
  • Evaluate the contribution animal models made to the discovery
  • Describe the design of the biological therapeutics  cA2 and infliximab
  • Relate these to the proof of concept clinical trial for cA2, and the ATTRACT infliximab trial. 
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Answer :

Assignment Title- TNF and Rheumatoid arthritis

1. Introduction

A deep research of patients who are suffering from what is known as TNF (tumour necrosis factor) has resulted in some amazing results. An end to end method of study has been adopted which can reveal some result about primary path physiological research. A study of debilitating inflammatory illness inclosing the initial stage of chronic level of RA (rheumatoid arthritis) was made to know more about it. As compared to all previous types for RA study which evolved originally from serendipitous pronouncements, the TNF patients describe the principal “rationally based” method, as well as one first approved FDA recombinant biologics or proteins for the cure of RA.

2. TNF as a disease and Subject of TNF

 Basically, TNF was known for its capacity to start necrosis of removed tumour infected cells in rats. The cloning and purification of a unit named “cachectic” that makes wasting in persistent diseases, was finally found to be similar to TNF-a. Tumour necrosis factor was come into existence originally by macrophages and by lymphocytes to a limit. It is an example of 17 known fragments of a class of polypeptides that combined with the respective class of patients (Zwerina et.al., 2011). These ligands are predicted to have ten b-sheets that are forming a range, and including -b, TNF-a, lymph toxin- and CD40 ligand, along with Fas ligand, and others (Table I below). Tumour necrosis factor-ais initially manufactured and represented as a Tran membrane unit, the extracellular part of which is consequently cleaved by TACE (TNF-converting enzyme) to deliver the soluble 17 kDa unit. TNF-circulates in its soluble nature, work as a homotrimer and employs its cognate subject on surfaces of the cell.

3. Development of TNF Inhibitors

There are two strategies for TNF inhibiting that have always been most widely studied till date consists of anti-TNFmonoclonal antibodies and solvent subject TNF (TNF-R) (Table II). Both constructions will probably bind to reporting TNF-a, thus defining its ability to fight cell membrane-bound activate inflammatory and TNF subject pathways. Solvent TNF-R, simply not anti-TNF immunoglobulin’s would further is required to join lymph toxin (Feldmann, 2012). [An alternative strategy is to produce a TACE inhibitor to limit the number of circulating solvent TNF.]

4. Animal Model

 CIA Studies in Mice

 CIA popularly known as Collagen-induced arthritis in the mice is caused in vulnerable mice strains by immunization with second type of collagen. Arthritis is a type of macroscopically occurs up to 35 days after persists for a few months and immunization until the joints get amylose. Collagen-induced arthritis shares some histopathology kind of features with RA, including synovial cell and mononuclear cell infiltration hyperplasia occurring in panes structure with cartilage and bone destruction. 

In both CIA and RA, disease perceptivity is described by auto reactive T cells, and MHC class II alleles are projecting in the joint with confinement in VbT cell receptor use (Feldmann and Maini, 2013). As most of such similarities, the CIA has been used the widely new model for RA.

Despite of some differences with RA issue in human, these models of animal are strongly supported in TNF as a crucial target for intervention of therapeutic.

5. Human Clinical Trials

For the purpose of the safety of TNF in humans was unidentified, trials in early period for RA patients with targeted issue. In case of disease which is longstanding that had futile to respond correctly to conventional treatment like gold salts, methotrexate, immunosuppressive and similar types. Now days, to take care of such patients the target is to select who are young as well as adult and are suffering from RA of initial stage (Van Schouwenburg et.al., 2013). A fruition of this study is based on these results has further focus on some clinical parameters as last point of focus.

With some updated trials, the area of focus will be radiographic (structural) endpoints.

Data of some of the clinical research that has been led by the FDA for remedy of RA in two therapies will be showcased. These factors to be considered are:

Etanercept – This is a soluble receptor of p75 TNF which is linked to Fc part of IgG

Related results that are evaluated in clinical claims of possible treatments for RA involve composite records, and peculiar clinical parameter, that works to integrate clinical records, and multiple radiographic scores.

Infliximab – Mice and human structure for treatment and research of anti-TNF antibody for human.

Though, the “standard gold ” for the purpose of assessing the effectiveness of the practice in rheumatoid disease is its capacity to reduce or prevent radiographic series of the attack – that means, the procedure must reduce or prevent the expansion of new or increasing erosions and reduce the expansion of progressive as well as new joint for narrowing the space. Several system of scoring had been made for supporting such radiologic signs of RA.

Etanercept as well as infliximab both are extensively studied for human body, and FDA has now approved this treatment for RA. As extensive studies had been performed by doing innovative researches about the treatment, only patients who were have long-standing type of persisting RA got identified and processed for evaluating such outcomes.

Though most of such patients got negative result in multiple traditional examinations of RA (like gold, methotrexate etc.), responses of clinical for these TNF inhibitors were highly rapid as well as robust.

With this new technology people who are suffering from this kindof disease are being targeted for doing respective research. Results of these researches are being quite robust. It has been found that more convincing type of radiographic information for the study of initial and last stage disease in many patients can be cured with the help of these newly developed anti-TNF medication. This medication will work to reduce the effect of damage and at the same time it will work to improve the overall health of person suffering from such radiographic damage.

6. Conclusion

These researches are offering the ultimate “proof of concept” for everyone and it shows that anti dote for TNF is really a crucial of joint damage in pathogenic mediator along with RA (Alexopoulou et.al., 2017). Though may be it has been one of the most fascinating fact about these researches which are targeting a single inhibiting cytokine can intensely alter the normal history of such disease.