A paper I recently read from a group at the National Institutes of Health, has addressed the immunogenicity issues as they relate to the toxin via mutating large hydrophilic amino acids on the surface of their toxin. This group used an immunotoxin BL22, which was previously shown by their group in clinical trials to be successful in inducing remission in patients with drug-resistant Hairy cell leukemia. "BL22 targets CD22 positive malignancies and is composed of an anti-CD22 Fv fused to a 38-kDa fragment of Psudomonas exotoxin A."
The group found that they could mutate eight residues of the toxin and still maintain the cytotoxicity of the drug, but decrease the immunogenicity and antigenicity in mice ( I have further read in the literature this drug is now in clinical trials as well). Overall, this appears to be a better drug than the parent BL22 and still retains the efficacious cytotoxicity desired for a a cancer drug.
Questions that I have regarding immunotoxins are:
Now that the immunogenicity and antigenicity issues regarding the toxin have been somewhat addressed, will these drugs be more effective in patients with solid tumors? Patients with solid tumors were previously reported to not have successful outcomes with immunotoxin drugs due to their ability to elicit neutralizing antibodies, whereas patients with B and T-cell malignancies were unable to do this because their immune systems are suppressed.
There does not appear to be a consensus between the current FDA approved drugs regarding the type of monoclonal antibody used
Bevacizumab--humanized monoclonal
Cetuximab--chimeric monoclonal
Panitumumab--fully human
BL22 or HA22--unable to find
I am wondering if any of you think that by using the least foreign monoclonal antibody ("fully human") and a toxin where the epitopes have been removed to the degree that the antigenicity and immunogenicity is minimized, but the toxin retains full cytotoxicity, could these drugs be more suitable for treatment of solid tumors?
Onda, M., R. Beers, L. Xiang, S. Nagata, Q. Wang, and I. Pastan. An immunotoxin with greatly reduced immunogenicity by identification and removal of B cell epitopes. PNAS (2008) 32(105): 11311-11316.
Thank you for introduction to what seems to be a great concept and soon a clinical reality!. I was wondering if the neutralizing antibodies that the solid tumors produced, were they Abs against the cytotoxin or against the cytotoxin attached antibody. Also wouldn't blood circulation related exposure in solid tumor be an issue (less tumor surface exposure less interaction with Cyttx+Ab) or is it that once inside the body Cyttx+Ab get released in the tissue freely?
ReplyDeleteI wonder if one of the reasons for the increased efficacy for the leukemias/lymphomas is their higher rate of cellular division compared to the slower growth of many solid tumors. It would make sense that in a highly active cell, an agent that targets protein production would have more significant results. But I think you make a good point about the modified agents and potential applicability in the realm of solid tumors. Any data out there yet with these new immunotoxins and solid tumors?
ReplyDeleteI like this topic Tanya! My impression is that immunotoxins are less effective in treating solid tumors because the immune system is less compromised and Abs develop against the immunotoxin. Is this correct? If so, it does seem that eliminating some of the B cell epitopes on the immunotoxin would make it less recognizable to the immune system. However, it also seems that this would decrease the anti-tumor activity...? What do you guys think?
ReplyDeleteHarmonical contrast and Amy, yes the literature states that the antibodies produced are against the cytotoxin used, which is the suggested reason that they are less effective. In the paper, they were able to maintain the anti-tumor or cytotoxic activity even though the eliminated the B cell epitopes, but I thought that exact same thing when I was reading the paper, until I read the section on the maintained cytotoxicity. But I think that the rational is that by removing the epitopes you don't remove the toxic portions, only the portions that are recognized by the immune system. My guess would be that when genetically modifying the toxin you would need to be careful that the epitopes you are removing and not necessary for toxicity and are only for immune system recognition.
ReplyDeleteSteve, I am unsure if there is any literature on the new immunotoxins and solid tumors, it seems like the focus has been on leukemias and lymphoma's because that's where the original success was, but I do think that with new combinations there may be more success in solid tumor therapy, least I hope specially with the success these immunotoxins have.