Bispecific antibody constructs are an emerging field in haematology, oncology and infectious disease. The lead compound in this new technology is blinatumomab or the BiTE technology. BiTE means bispecific T-cell engaging antibody construct and it’s a platform technology because you can use a respective target. For example with blinatumomab it is CD19 that is expressed on B-cell malignancies including also ALL and this has now been so successful that this kind of approach has led EMA to actually have a positive view in a registration trial of blinatumomab. So it’s available now in several European countries and also in the United States, Canada and Australia.
But this is only just the first product that has made it all the way so on the platform technology, using the BiTE platform technology, obviously there are clinical trials being performed now in other malignancies including AML, multiple myeloma, by instead of targeting CD19 on the cell surface of the cancer cells targeting, for example, CD33 for AML or BCMA on multiple myeloma. Then obviously the blinatumomab is actually a very small compound, it just takes out the VL and the VH region of the respective antibodies. It’s a fusion protein of, on the one hand, the VLVH region recognising CD3 and the VLVH region recognising the CD19. It’s just a very small linker of about eight amino acids so it just gives it a lot of flexibility in that [?? 2:11].
So it’s easy to envision that you can have different formats. So, for example, a format that would include two binding agents instead of just having one VH and one VL region targeting CD19, it could be two VH and VL regions and also on the CD3 side it could be a format where you envision having a complete antibody, the normal Y-shape where on the one arm it is attacking the cancerous cell and bringing in the T-cell. So all these different constructs are now being developed for mainly B-cell malignancies, because obviously the field is most advanced in that context, and now also in clinical trials. But they have shown in preclinical models in mice and also in monkey to be quite able to deplete B-cells very quickly, within hours after giving the antibody constructs in this situation, and also resulting in proliferation of T-cells as they engage then with the B-cells in the monkey.
Saying that, using these different antibody constructs it also has different pharmacological differences in terms of PK in those animals. So blinatumomab, for example, is very small or the BiTE platform is a very small molecule and we have a very short half-life of about two hours; it gets renally excreted. The way it is applied now it is by continuous infusion to the patient. These other constructs, all the way up to a complete full length bispecific with the IgG format, will have completely different PK in the humans, in the human trials, hence the way that it’s applied it’s more not in any continuous infusion more than a four-hour infusion, three-hour infusion, more like a traditional way when we apply antibodies to our patients. So that means that the handling of these bispecifics can be very different and there’s ongoing work in progress to understand in patients how can stable PKs be established with these different formats, different to blinatumomab which is a continuous infusion in that context.
So that is one level of complexity. The second level is that the VL and VH regions which are the basis for all these bispecifics may differ quite considerably in the on and off rate of their targets. For blinatumomab, for example, the CD3 proportion of the construct has intermediate affinity so it doesn’t stick very well to the T-cells. So what happens is blinatumomab first goes to the B-cell and then the T-cell which sort of prowls around will then be sucked in in that situation. Then some of the other constructs it’s just the opposite – the affinity towards the CD3 is much higher so the T-cells get saturated with it and are more or less carrying with them the bispecific stuck on the cell surface and then engage with the B-cell that they might find. So to which degree that is going to have an impact on the efficacy of the drug and what kind of toxicity is to be expected is completely unknown at this stage.
The next level is there are also some constructs which instead of using CD3 or T-cells as their effector mechanisms they use NK cells. So there’s one construct that, for example, uses CD16A as their binding domain which is expressed in NK cells and there are clinical trials that already have been performed with that demonstrating in Hodgkin’s lymphoma that that can be active and it’s now in a phase II trial. So using different effector cells in that context.
It’s a very interesting field at the moment to understand on the level of all these different levels which construct or which platform technology might be most suited to treat haematological malignancies or overall cancer. There might be a big difference between targeting lymphoid malignancies because lymphoid malignancies do sit in the lymph node, in the bone marrow, natural spaces where T-cells and NK cells travel through at very high level whereas solid tumours there’s definitely less T-cells going into that tissue and it’s easy. It’s a very interesting question how that will have an impact on the efficacy of these drugs down the road in that context. It could well be that we are ending up at this [?? 7:57] suitable drug platform for haematological malignancies but not for oncology in that context.
Could you tell me more about the combinations in PD-1 therapy?
Yes, checkpoint inhibitors or the whole family of checkpoint inhibitors, and it’s not just anti-PD-1 but it could be also [?? 8:21] might be very interesting to explore if inbuilt resistance mechanisms can be overcome adding anti-PD-1. It’s quite conceivable because if a T-cell gets activated it starts producing cytokines. Some of these cytokines like TNF and gamma interferon do induce, for example, PD-L1 expression on cancerous cells. So hence if you could block that you maybe still overcome inbuilt resistance mechanisms and perhaps the bispecific therapy might be even more effective in that context.
I’m aware of one clinical trial actually at the moment, or two, that are going to look in that direction in B-cell malignancy studies. So it’s going to be very interesting to see what’s going to happen down the road.
