Inotuzumab sinks....

Inotuzumab flops in DLBCL

I am very excited about a new class of investigational therapies called "antibody drug conjugates (AKA. ADC's".(see my prior post on these fascinating drugs).  In essence these are "smart bombs" compared to old school chemotherapy that goes after just about everything. 

An ADC is an antibody loaded up with powerful chemotherapy.  Once infused, the expectation is that the antibody will help deliver the chemotherapy directly to the tumor cells sparing healthy tissue.

Scientists have been playing with this concept for many years.  In fact Paul Ehrlich initially proposed the idea in the late 1800's before we even knew that antibodies existed (visionary!).

The first drug ADC approved was myelotarg for acute myeloid leukemia (a much more aggressive disease than CLL/NHL).  Unfortunately, the drug had some significant side effects including liver damage and the drug was pulled off the market although recent studies may bring the drug back to life.

The team at Seattle Genetics extensively studied the science of how to use an antibody to deliver chemotherapy specifically to cancer cells and came up with brentuximab.  This has been a quantum leap in the management of Hodgkin's lymphoma.  Once the science of the linker and chemotherapy was solved - solving a new disease was simplified to finding the right surface marker on the cancer cells.  That is a science that is pretty advanced in CLL/NHL and now a host of companies are developing drugs in these diseases.

Genentech just got another such drug approved in breast cancer called traztuzumab-emtansine (T-DM1).  This is a big step forward in patients with breast cancer and a particular marker on the surface of the cancer cells.

Meanwhile, Pfizer (who made myelotarg) continued development using the "myelotarg technology" but turned their attention on B cell cancers.    Inotuzumab used a different antibody but the same drug and "glue" (the linker that attaches the drug to the antibody).  The drug looks very active in acute lymphoblastic leukemia and development continued in DLBCL.  Unfortunately - in a press release out today it looks like the drug failed to improve outcomes sufficient to justify continuing the trial.

We are fortunate however that a number of companies have seen the success of brentuximab and are looking to make their mark on B cell cancers.  I can think of about a half dozen drugs that are being studied in NHL. While inotuzumab didn't pan out, I think it used the most primitive technology out there.  The remainder of the research drugs out there use the 2.0 technology (smarter linker / drug).  It will be exciting to see how these influence outcome!

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.