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Sunday, October 06, 2002

10 seconds ago I had an idea. Maybe in 10 seconds I will see what is wrong with it, but right now I like it a lot.

problem: when we need a killer t-cell response we only make antibodies which don't do the job.

Proposed solution: Make a peptide which has the fab part of the antibody fused to some peptide which just drives our killer cells nuts with fury. Inject it. the peptide goes and sticks to the target (no big deal we already have antibodies doing it). There it sits waving it's tail end which is like a red flag to a bull. The killer cells come and kill the target.

Why not ? Makes sense to me.

Now to work we need activated (or memory) killer cells around. The red flag will not be presented on an antigen presenting cell. That means must pre-stimulate with some known peptide to get memory killers of right type.

Problem includes tumours and HIV infected cells so two really big problems.

OK now more than 10 seconds have passed and I see what's wrong with the idea (was a very exciting minute anyway). HLA restricted. Ugh. seems would at least need a different construct for every HLA type. So the known peptide could be HLA type 1 presented by HLA type 2.

Back to drawing board. First could there be a more general red flag ? Like a monoclonal which sticks to CD8 and constant region of t-cell receptor ?

Like some peptide which happens not to give a killer response as HLA restricted as usual ?

Or maybe the plan is a huge massive semi mechanised hybrid construction project. We want Fab end sticks to HIV infected cells (or lung cancer cells) and red flag end looks like HLA type 1 presented by HLA type 2 through N (N is number of HLA types) or HLA type 2 presented by HLA type 1.

I'm thinking as I type so this is getting long.

New idea

There are monoclonals which stick to something we don't like and want to kill (cancer cell or hiv infected cell).

We each have memory type killer cells waiting to kill something (different for each of us which is the problem).

Now what about helping me Robert Waldmann (so far I don't have any cancer I know of and don't have HIV but I am being honest about how time consuming the project is becoming) Can we make a red flag which activates a memory type killer cell which I already have ? Well if we are making a peptide, probably best approach is not to try to make peptide presented by HLA but rather an monoclonal which sticks to and activates a memory type killer already there.

Question: Are there known monoclonals stick to t-cell receptor andactivate memory type killer cells. If not not so helpful to go on. It seems to me it should be possible.

OK new peptide to kill target cell is monoclonal sticks to target cell linked to monoclonal sticks to AND stimulates t-cell receptor of a memory type killer cell.

Notice the change. As someone who never managed to construct a construct, I am reluctant to propose constructing a large number (number of targets
times number of HLA types). Now the link the monoclonal which sticks to target to the red flag for killer t-cells is a link to protiens. Indeed
they are antibodies so can make a hybrid by breaking S-S bonds and remaking them. That is current version of idea works without using restriction enzymes or ligase.

So for proof of principal the stick to target AB could be something which sticks to some other leukemia (easily accessible cells).

The red flag AB is make antibodies to t-cell receptor of memory t-cells (Isolated by FACS) and screen for agonist antibodies which drive them into a homicidal (sorry cytocidal) fury.

Link ab's inject and hope.

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