Friday, July 13, 2012

Immunoconjugate Drugs

Drug Update

ASH 2012 CD22 ADC update 
ASH 2012 CD79 ADC update

One of the technologies I am most excited about right now are a family of drugs known as "antibody drug conjugates (ADCs)."  I think these compounds may begin to fulfill the dreams we had years ago of effective and non-toxic treatments.

The basic idea is the following.  Take a monoclonal antibody.  You make antibodies to fight off flu, cold viruses, bacteria, etc.  Instead of a naturally occuring antibody, we use technologies that make them target lymphoma or CLL cells.

That is the idea behind rituxan.  The antibody coats the outside of the cancer cell and tells the rest of the immune system to attack the cancer cell.

Depending on the target though, sometimes the antibody gets swallowed by the cancer cell instead of just coating the outside.  Once it gets swallowed, a special part of the cell called the lysozymes helps break the molecule into little pieces.

The true innovation of these drugs is the "linker" segment which allows you to attach super potent chemotherapy to the antibody so that the two are effectively "glued" together until they hit the lysozymes.  Once the ADC binds to the cell and gets swallowed, the super potent chemotherapy is released exclusively into the cancer cell instead of going throughout the entire body.

There have been a handful of these drugs out there for a while.  A well known success/failure is gemtuzumab (aka myelotarg).  This was initially approved by accelerated mechanisms for Acute Myeloid Leukemia, then revoked by the FDA when confirmatory studies failed to support the initial enthusiasm.  Frankly this drug will likely come back but only after we are more confident we know how to use it right.  In some regards, Ontak is sort of the same idea.  One can even put zevalin in this category but here you used radiation instead of chemotherapy and that made it logistically difficult for practices to administer what is a very effective treatment.

The problem with the early molecules was that the linker was not so good and free drug got loose in the body.  In the case of gemtuzumab that caused a lot of problems with the liver and low blood counts.

The folks from Seattle Genetics seem to have solved the linker issue.  Their first approved drug - Adceteris / brentuximab is truly revolutionary in Hodgkin's Disease.  Targeting CD30 (a marker for HD or Anaplastic Large Cell Lymphoma), this well tollerated single agent gets durable remissions in patients whose cancer has been refractory to just about everything else.

We have also found CD30 shows up on a number of non-hodgkin's lymphomas.  This was presented at ASCO this summer.

Brentuximab vedotin for relapsed or refractory non-Hodgkin lymphoma: Preliminary results from a phase II study.

They have licensed the technology to a number of other companies and now a host of drugs are working through the system.  An entire class of drugs is now working their way through the system that may prove to be effective in patients with CLL/NHL.  I wager that these drugs are going to be quite active and offer a new type of treatment for patients at all stages of disease. 

Genentech has a little video series for the interested reader - excuse the commercial reference.