Saturday, May 18, 2013
New treatment for melanoma!!!! - ADC's - Antibody-Drug Conjugate
New scoop!!!! New trial!!!! So...what the heck is an ADC????
ADC and the NCT01522664, Phase I trial, Genentech/Roche, ADC, Antibody Drug Conjugate DEDN6526A
An ADC (antibody drug conjugate) is like a Trojan Horse!!! It takes a bad ass cytotoxin, like auristatin (that's the one being used here), an anti-mitotic agent that derives its action by preventing tubulin polymerization and therefore stops cell division, attaches it via a special molecule to a monoclonal antibody that targets antigens preferentially expressed on the surface of the targeted cancer cells..in this case, Endothelin B. This method allows patients to survive being treated with really toxic agents without suffering the terrible side effects that would certainly ensue should those cytotoxins be injected directly. By taking them under cover, only the bad cells we want to target are damaged.
ADC's have been in the works since the 80's. Over that time laboratory researchers have found many more possible antibodies to use (and studied which tumors express them the most) and a variety of gradually improving techniques to "link" the chemotherapeutic agent to the antibody. Improved "linkers" seem to have made it easier to use a variety of antibodies as well as cytotoxic agents while keeping the whole little trifecta intact until it reaches its destination. Patent information seems to indicate that researchers feel they may even be able to target infectious organisms in the future. Two ADC's have been marketed for lymphoma and leukemia. And, just a couple of weeks ago, Celldex got FDA approval for CDX-011 (glembatumumab vedotin) as a treatment for Her-2 breast cancer. Interestingly, initially, this drug which uses "auristatin conjugated to a monoclonal antibody that recognizes GPNMB, expressed at higher levels in melanoma and breast tumors" was tested in patients with melanoma as well as breast cancer. Sievers and Senter, in a Seattle Genentech report state, "In a phase I/II trial in patients with unresectable late-stage melanoma, CDX-011 showed overall response rates ranging from 14% to 19% depending on dosing frequency and GPNMB expression levels." However, at this point, it seems that this particular ADC is no longer being utilized in melanoma trials.
Back to the ADC at hand...Genentech's GR-7636: This drug targets Endothelin receptor ETB, which is apparently expressed on most melanoma tumors (as well as skin cells in general....and is even in the pathway for their embryonic development....which explains why one of the side effects can be skin irritation and rashes). So much so...that at first folks tried the drug bosentan, a dual endothelin A/B receptor antagonist which is similar to anti-PD1 in that it uses an antibody to modify a specific cell receptor, but UNLIKE anti-PD1, the receptor is on the melanoma cell itself, and the hope was that by antagonizing it [blocking it] the cell would die....while anti-PD1 hopes to activate white cells and bring the immune system to attack the tumor cell. Anyhow, they tried bosentan alone and combined with dacarbazine but had disappointing results.
One other note on Endothelin B and its expression in melanoma cells: In the Asundi paper: They assayed the amount of cell expression of the receptor and found it to have a range of expression from 1500 to 33000 per cell line. In their mouse model, they showed efficacy of their ADC for both the low and high end of cell expression.
So.....it seems that researchers have found a very melanoma specific, cell surface receptor, which provides a target using antibodies bonded to a highly potent cell toxin which is rapidly taken in from the cell surface and converted to the active agent inside the cell. Theoretically, this will allow targeted delivery of extremely cytotoxic agents and in the mouse model produced rapid (i.e. one week) death of melanoma cells with no recurrence for three months. Luckily, a dear one of mine, is embarking on this rattie adventure at Sarah Cannon in Nashville. There, though they are only reporting on 15-20 patients currently enrolled, they say that they have determined the most effective dose and schedule, side effects have been minimal, responses are clear (or not) by 6 weeks, and are attaining about a 30% response rate. Due to the explanation above, prior ipi or anti-PD1 is NOT an obstacle since this regimen works in an entirely different fashion. Recruitment is apparently 1 patient per every 3 week cycle, per trial site.
Wishing you the best in your rattie adventure, J. Hang tough, all of you. - c
An antibody-drug conjugate targeting the endothelin B receptor for the treatment of melanoma.
Asundi, et al. Clinical Cancer Research. 2011 Mar 1;17(5):965-75 Genentech, Inc, San Fran, CA
Antibody-drug conjugates in cancer therapy. Sievers and Senter. Anne. Rev. Med. 2013. 64:15-29. First published October 3, 2012. Seattle Genetics, Bothell, Washington.
Antibody-drug conjugates. Zolot, Basu, Million. Nature Reviews. April 2013, Vol 12.
Maturing antibody-drug conjugate pipeline hits 30. Mullard. Nature Reviews. May 2013, Vol 12.