Generation of BiKEs and TriKEs to Improve NK Cell-Mediated Targeting of Tumor Cells
Christina Lingham:
Hi my name is Christina Lingham of Cambridge Healthtech Institute, we're speaking today with Dr. Jeffrey Miller who's a Professor of Medicine in the Division of Hematology/Oncology and Transplantation, and Deputy Director of the Masonic Cancer Center at University of Minnesota.
Dr. Miller is a speaker at the PEGS conference, and his talk is on generation of BiKEs and TriKEs to improve NK cell mediated targeting of tumor cells. Dr. Miller, thank you for speaking with us today. Can you outline, what is considered to be some of the greatest obstacles to developing BiKEs and the new class of molecules called TriKEs.
Jeff Miller:
I guess I don't see many obstacles, I think the biggest issue that we have been dealing with is we have a platform that works in vitro, where we can engage NK cells, we can give them specificity to targets, and we can have an IL-15 in the TriKE platform. Which is by the way the one that we are going to pursue clinically because it is so much better than the BiKE platform, this added IL-15 activity in the molecule.
We have good in vitro activity, we have good small animal data, and the biggest issues now is to get it into a clinical trial, which we hope to be treating patients sometime by the end of the summer. I say that because we're in the process, hopefully within the next four weeks of getting the final IND to the FDA on the first TriKE molecule, which would be CD16 specific, CD33 specific and with an IL-15 linker between them.
Christina Lingham:
Can you describe your method and what unexpected discoveries you've made?
Jeff Miller:
Yeah I think that the biggest difference, and this is really outlined in a clinical cancer research paper that was published last year. The thing that surprised us the most is that when you look at the BiKE platform, which is CD15, an irrelevant or inert linker, joining that to CD33, we clearly were able to re-target NK cells to leukemia targets with specificity. But what we were surprised is that that delivers zero proliferation to the NK cell.
I think one of the things that I pointed out in the talk for the group is one thing that we have learned from the TCR experience, you know the genetically modified T-cells, is that these TCR constructs give you antigen specificity in a proliferative signal. With our BiKE molecule we get antigen specificity but no proliferation, and I think the most unexpected thing is when we substituted the IL-15 linker in the TriKE molecule, we can now get antigen specificity and proliferation in the same molecule. I think that the biologic hypothesis here is that for NK cells need to work, they need to be sustainable and targeted at the same time.
Christina Lingham:
And what's unique about your approach?
Jeff Miller:
We're not aware of any other monoclonal antibodies, whole antibodies, trastuzumab, rituximab, they engage CD16 on NK cells, but they don't deliver any proliferation. So I guess the issue is that within one molecule, we give antigen specificity through the CD16 receptor, and we give a proliferative signal at the same time. So I guess the drug is really intended to amplify the effectors at the same time as driving their specificity to targets. And that's what we think is unique. To my knowledge there is really nothing out there that reaches that same goal.
Christina Lingham:
And what advice do you have for people introducing novel antibody therapeutics in the clinical setting?
Jeff Miller:
I guess my advice is, what we've tried to do in our developmental pattern is make sure we learn as much biology as possible. As you guys are probably well aware, the field is getting very, very competitive. We're in a great time for immunotherapy, I think everybody recognizes the power of immunotherapy. I guess people are trying to develop constructs, they need to really think about what biological question they're trying to answer. What is going to be unique about the molecule. We've been very clear that we know our goals. Our goals have been antigen specificity, NK survival, and proliferation, and we've been approaching the design and future modifications, by the way, to enhance those features.
I guess that my recommendation to others is be clear about the biologic question setting off your new molecule, and why it will be unique in the field. Because this field is growing and there are lots of good ideas out there. But the end of the day, carefully designed clinical trials are really what's going to drive the field forward, or any new idea for that matter.
Christina Lingham:
So what are some of the most exciting new developments emerging for bispecific antibody killer engagers?
Jeff Miller:
So what's really driven the field in my mind, and I am a hematologist, I still take care of leukemia patients. What's really driven the field is blinatumomab. We clearly have a molecule, a CD3/CD19 engaging molecule that drives T-cell specificity and proliferation. I think that that has really set out as really kind of a unique paradigm. So there's a whole bunch of interest in the field, in developing immune engager complexes that have various functions. Some are designed to have a better half life than our current TriKE molecule would be. Some are designed to engage more than one agonistic molecule on the lymphocytes. And I think what's clear is that we have proof of concept with CD3/CD19. Now the question is, can we harness this and I think the holy grail for anybody either getting into this as part of laboratory based investigation, or even clinical investigation is can we extrapolate and get some of these molecules to work in common solid tumors.
Christina Lingham:
Thank you Dr. Miller. Dr. Miller was a speaker at the PEGS conference on generation of BiKEs and TriKEs to improve NK cell mediated targeting of tumor cells. Thank you for joining us.
For more information about the PEG Summit and for next year's dates, visit pegsummit.com. Thank you for listening.