Thank you bennevisplace for posting about AstraZeneca's monoclonal antibody clinical trial for AZD7442! AZD7442 would likely be a safe and effective prophylactic treatment for us!
Reading about the development of AZD7442 led me through several incredibly detailed highly technical publications that highlighted just how much work went in to the selection and development of this monoclonal antibody combination! And the best part is that AZD7442 is basically just like a Rituxan or Gazyva infusion, only directed towards the SARS-CoV-2 spike protein rather than CD20.
To summarize the work:
Memory B cells were isolated from COVID-19 patients and cultured in vitro.
Strategy 1:The antigen reactivity of secreted antibodies from individual B cells was measured for thousands of cells. The heavy- and light-chain genes from single antigen-reactive B cells were sequenced and cloned into immunoglobulin expression vectors. (78 antigen-reactive mAbs were cloned at this step)
Strategy 2: IgG genes were sequenced and cloned from individual B cells without prior screening. 389 recombinant SARS-CoV-2-reactive human mAbs that expressed sufficiently well as recombinant IgG to characterize the activity of the mAb were selected.
The recombinant monoclonal expression vectors produced by both strategies outlined above were transfected into Chinese Hamster Ovary Cells (CHO) and the resulting monoclonal antibodies went through extensive screening.
Heavy and Light chain genes from the candidate monoclonal antibodies were linked so that they could more efficiently be expressed in the CHO cells leading to more efficient industrial production.
The two monoclonal antibodies ( COV2-2196 and COV2-2130) chosen for AZD7442, bind simultaneously to the SARS-CoV-2 Spike protein recognizing non-overlapping sites, neutralizing wild-type SARS-CoV-2 virus in a synergistic manner.
1. Rapid isolation and profiling of a diverse panel of human monoclonal antibodies targeting the SARS-CoV-2 spike protein
I had Rituxan about 5 years ago for my CLL. I did not have any troubling side effects; no vomiting or nausea. To date I have been symptom free. I have had CLL for 11 years; fingers crossed for another 20 years! I wish you good health and happiness!
Thank you for an excellent explanation that puts the new drug into context with other monoclonal antibodies that some of us are more familiar with. The Nature paper was really dense.
The impressive thing to me is how they can select just the right B-cells that make antibodies for the infamous spike proteins. The same technique could be used for any new and different infection that comes along.
I do wonder how much this drug will cost, and how long it will provide protection.
Great stuff, thanks for taking the trouble to pull all this fascinating information together for us. I had no plans for the weekend, so I guess this will be it!
To follow up on this thread, UK-Sparky and I are two members who have applied to join the Provent phase 3 trial in the UK. Provent is the trial of AZD7442 as a prophylactic, and the trial is also being conducted at 102 sites in the USA clinicaltrials.gov/ct2/show...
For immunocompromised individuals is there a risk that MAB treatment, even if given at an early stage, could be counterproductive by driving viral evolution, as has been observed with convalescent plasma therapy? medrxiv.org/content/10.1101... There's another well documented case study of an immunosuppressed blood cancer patient with SARS-COV2 infection for many weeks. The course of the infection featured few symptoms, failure of antibody treatment and evolution of the virus cell.com/cell/pdf/S0092-867...
In terms of the AZD7442 trial, I would have signed up for it, if not for being excluded by my ongoing IVIG infusions.
It is very difficult to draw conclusions from the limited studies on the treatment of immunocompromised patients with convalescent plasma. For one thing, the level of neutralizing antibodies in the plasma batches was not possible for me, with my limited experience with the terms used, to compare. But yes, it is indeed unsettling to think of the virus mutating away because we are not able to clear it!
"Furthermore, and importantly, an appropriate anti‐SARS‐Cov‐2‐neutralizing Ab activity titre should be verified."
The Euroimmun assay, which was used in one study to which you referred has a reported specificity of 96.8% whereas another method of antibody specificity was 99.8%, which I guess means that non-SARS-CoV-2 antibodies could have been included in the antibody titer assays of convalescent plasma.
“Collecting and evaluating convalescent plasma for COVID‐19 treatment: why and how?”
Another paper reports that convalescent plasma antibody levels as determined by the EUROimmun assay should have a reactivity index of 9.1, whereas the CLL patient who received three infusions of convalescent plasma was administered 6.1, 7.1 and 6.1 plasma. Would it have made a difference if the titer would have been higher? We don’t know.
“Convalescent plasma therapy for the treatment of patients with COVID‐19: Assessment of methods available for antibody detection and their correlation with neutralising antibody levels”
Many thanks gardening-girl. These individual case studies are tantalising aren't they. As you say, difficult to draw firm conclusions from imperfect data. Phase 3 trials of treatment-MABs should tell us more.
In the same vein, today I listened on BBC radio "Inside Science " to two scientists incl a prof of immunology giving their views on the UK government's plan to extend the interval between doses of both the Pfizer-BioNtech and the Oxford-Astrazeneca vaccines from 3 weeks to 12 weeks - outside experimental limits - for the understandable reason it will give more people some AB protection sooner, in the face of the wildfire that is the new Covid variant. Both scientists were a bit concerned at the possibility of the very same thing happening: some people would contract the virus at a stage when they had dwindling antibodies, the virus would take root without causing symptoms and fester away to appear many weeks later in mutated form. They think it's going to be essential to run studies in the vaccination programme to monitor immune reponses longitudinally and also monitor emergence of mutants.
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