Crystallography of the B-cell receptor immunoglobulin in CLL patients

Prof Paolo Ghia - San Raffaele University, Milan, Italy

Would you be able to tell me a bit about your research that you presented today?

Yes, yesterday we presented the first study showing crystals of the immunoglobulin receptor stressed by chronic lymphocytic leukaemia cells. We focussed on distinct receptors which are those expressed by a so-called stereotype subset of patients. So these are receptors that are shared among more than three patients all over the world.

And what results did you present?

The study started and was planned because we wanted to understand what is the actual element that is stimulating the BCR, the immunoglobulin receptor in leukemic cells. Because there are two opposite hypotheses: on one side there could be antigenic elements, classic antigenic elements that bind into the immunoglobulin receptor stimulating it. Or on the other side it has been proposed that there could be a so-called autonomous signalling so the immunoglobulin can combine itself and then get stimulated without a real antigen. So we wanted to get an idea of what was going on. Indeed, to our surprise, we confirmed with the crystals that indeed in the few cases so far that we performed each immunoglobulin is indeed binding to itself. The interesting and the new finding is that indeed it is bound by each immunoglobulin is different in each distinct subset. So it is not only one epitope that is recognised by all CLL immunoglobulin as had been proposed in the past but it’s really selective and different in each subset of patients.

Can you tell me more about the techniques you used?

These are crystals, I’m not an expert of that because it’s a completely different branch of research so this is instead. In fact this work was done in collaboration with our crystallography unit. It all starts from the production of recombinant immunoglobulin in large quantities, in terms of milligrams. These are actually placed in a special environment where the molecule itself is crystallised. So we really produce crystals and it is very interesting and a wonderful phenomenon when the crystal is prepared then there are imaging techniques to visualise what is happening. In that particular crystal we saw that the immunoglobulin molecules are indeed binding to each other, creating even larger crystals.

How do you think this will affect how patients are treated or how new treatments are developed?

If we confirm this data and we can really understand also how this can be important for every single case of CLL then we could first of all understand how the disease originates, so the pathogenesis of the disease, and then it becomes quite obvious that somehow we could go and interfere with this binding between the immunoglobulin and itself and therefore we might plan and produce and design inhibitors or molecules that could interfere with the binding. This way the idea would be that the cells not receive any more signals through the BCR and therefore it should stop growing.

And what are your plans for future research?

The future research is first of all to expand the study, to produce more crystals from more subsets of patients in order to see if this is really a common feature of all patients, or at least most of the patients. Then the interesting point would be also to understand if this is the only signal they indeed receive or if maybe this is just a way to breach cells, leukemic cells, to bring leukemic cells together so that they can interact through other receptor cells, so other molecules. So this is what we are going to explore.

And is there any other information you’d like to tell about your research?

Only a part of the research that we are performing since many years about immunoglobulin receptors. I think that nowadays it’s quite clear, after 10-15 years of studies, that the immunoglobulin receptor is crucial for the onset and progression of chronic lymphocytic leukaemia and this has been also quite witnessed by the great efficacy of the new inhibitors that are indeed targeting the pathway downstream, the immunoglobulin receptor.