Thanks to a good discussion with Aussie Neil, MelioraDay and others I have looked further into the ROR1 story. As MelioraDay asserts, although ROR1 protein is on some healthy normal human cells, ROR1 antibodies are well tolerated and effective at inhibiting a survival pathway for CLL and other cancer cells. Even more exciting is that it can be “physically” combined with new novel agents and used as a delivery tool to bring cancer treatment to cancer B cells whilst avoiding harm to healthy lymphocytes allowing them to continue their life saving work.
Attached is an interview with Dr. Kipps from the Moore Cancer Center in San Diego on this exciting research.
Cirmtuzumab looks promising. Interesting that cancerous cells have ROR1 pathway activated (there to be used by fetal cells) and then normal cells do not have ROR1 so that the drug will target only the cancerous cells.
There's a diagram and description of how it works on the below page:
"Our studies show that published antibodies lack sensitivity to detect endogenous levels of cell surface
ROR1 by immunohistochemistry (IHC) in formalin-fixed, paraffin-embedded tissues. We developed a ROR1-specific monoclonal
antibody (mAb) targeting the carboxy-terminus of ROR1 and
evaluated its specificity and sensitivity in IHC."
In looking at this again today, I remember some information I learned many years ago about measuring the presence of carboxy-terminus of various proteins. I know many cells have proteins that are not "turned on" or active. For example there are active and inactive insulin molecules and various kinds of islet cells that are inactive. Both active and inactive cells can have measurable carboxy-terminus levels for various proteins. So I think this is a very complex issue. What we need to know is, and I am sure has been addressed is, does cirmtuzumab bind to all cells with this ROR1 carboxy-terminus, or just active cells? More questions come to mind about this than I have any answers to. I also seem to remember asking this question of Dr Kipps many years ago, was satisfied with the answer and put it out of my mind. I can't now tell you the answer but I will see him again in December or January and will get the details and his latest thoughts on this issue. I will post about it on HU. I also know that for any treatment to be approved, a literature review is completed by the researchers and the FDA from reliable, reproducible data bases such as PubMed, Embase etc. The research you sited would come to light and would have to be addressed in a satisfactory manner before any approval would occur. I think it is important to note that no toxicities regarding possible off-tumor targeting by cirmtuzumab have to date been found in human trials.
I think it's important to note also that the research sited above was done in primates, not humans, and I have been unable to find any other published research since then (2016) about ROR1 expression in normal human or primate cells. It may be there, but I can't find it.
So all that said, I have been following the research you mentioned in this post today for a while. Being able to put a payload of potent chemo onto cirmtuzumab that would deliver that chemo only to the cancer cells is a pretty excited field of research! Thank you for posting.
It is seductively very interesting and complex. Dr. Kipps who I know mostly through friend and colleague Brian Koffman’s tireless work seems to suggest that chemo as well as novel molecules could be attached to ROR1 antibodies.
When you say active cells, I take it to mean cancer cells or other rapidly dividing cells. That would be good to know and if just active cells it helps to understand the tolerability of Cirmtuzumab and would make this “messenger”/delivery vehicle all the more tantalizing.
I don’t know why exactly that John Byrd dismisses this so flatly, I am seeking him out for further understanding. Do keep us informed of your knowledge and insight into this seemingly enormously important treatment modality.
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