Saturday, August 18, 2012

Building a better CD20 antibody?

Rituxan was an unbelievable breakthrough drug in the treatment of all sorts of B cell lymphoid cancers (CLL / NHL) as well as a lot of autoimmune conditions to boot.  At the time it was put into the patients, the idea of using therapeutic antibodies to treat cancer had not really been done.  Skeptics abounded.  As soon as it was tried, it was immediately obvious that there had been a breakthrough.  One theme I continually revist is that the immune system can be a very powerful cancer fighter when properly directed.  Rituxan was one of the first ways to focus this aspect of the immune system to fight off lymphoma.

You make antibodies to fight off the flu, e. coli, etc.  Instead of the naturally occuring variety of antibodies, rituxan is a synthesized antibody designed to fight off B-Cells (ie. the cells that give rise to lymphoma and CLL).  Rituxan binds onto the outside of the cancer cell (on a marker known as CD20) and has about 4-5 ways to kill the cell. 

15 years later, hundreds of thousands of patients have been treated.  As a single agent nearly 70% of patients with untreated follicular lymphoma will respond and in many cases the responses can be very durable.  In most situations where giving chemotherapy for CLL/NHL is good, giving it together with rituxan is better.  Not bad for a drug that has few of the side effects of traditional chemotherapy!

Not long after Rituxan demonstrated its value, lots of science went toward understanding why rituxan does or doesn't work.  With the accumulated knowledge, different companies have sought to make a better version of the drug.

Ofatumumab was the next CD20 antibody to be approved.  The main improvements in ofatumumab was more sturdy binding to CD20, binding at a different location on CD20, and a better job "fixing complement."  Complement is a set of "executioner proteins" that get recruited from the circulation when there is enough antibody bound to the outside of a cell.  "Fixing complement" just means it does a better job attracting those proteins to bind to the outside of the cell and punch holes through the membrane.

GA-101 is an ant-CD20 antibody currently in clinical trials in both CLL/NHL.  GA-101 (aka obinutuzumab) does several things new.  It binds to CD20 in a different orientation.  Imagine an antibody like the letter "Y"  The top of the "Y" is the little "grabber" part that identifies its target while the bottom part of the "Y" sticks out and alerts the immune system.  GA-101 binds more vertically which sticks the action end out there better for the rest of the immune system to see.  Rituxan binds more flat to the cell and the action end sort of gets burried on the surface of the cell.  GA-101 also has a more flexible "hinge region" (where the "Y" splits) which is supposed to help bring together the different proteins better.  GA-101 also "engineers out" the complement activity and instead "engineers in" better ADCC.  ADCC (antibody dependent cellular cytotoxicity) is the term that describes when a "killer cell" attackes a target cell because it is coated with antibody.  Finally there is a somewhat poorly characterized process by which antibodies can cause direct cell killing.  This is supposedly enhanced by antibodies known as "Type 2" antibodies (not really worth explaining this one, except that Rituxan / Ofatumumab are Type 1)

So far, there are not a lot of studies that clinically compare the different anti CD20 antibodies head to head.  Ofatumumab initially tried to get an FDA approval in follicular lymphoma patients considered refractory to Rituximab.  Results didn't really impress all that much.   Based upon FDA approval strategies, it also tried to gain approval in CLL patients were refractory to fludarabine AND campath (or bulky fludarabine refractory where campath doesn't work well).  This worked better and led to the approval of ofatumumab in CLLThe drug has not yet gained a high utilization in CLL. 

GA-101 is owned by Genentech and with Rituxan likely to go off patent in the future, they are working hard to make GA-101 the standard-bearer.  At ASH 2011 there were a lot of clinical papers with GA-101 but the most notable was a head to head comparison of GA-101 to Rituxan in patients with relapsed follicular lymphoma.  GA-101 had twice the response rate though the duration of response was not a lot different.   Hard to say if that is a glass half full or half empty - trying to extrapolate to different NHL / CLL situations it may depend on the context.  Increasing a response rate in DLBCL might be very important whereas PFS prolongation may be more important in follicular lymphoma.  Furthermore, we should probably consider that the activity of one antibody may be better in CLL while a different set of characteristics may make a different antibody better in follicular lymphoma.

Perhaps the cleanest way to figure if a drug is active is in the previously untreated patients.  Ofatumumab was studied in this setting and reported at ASH.  GA-101 has been evaluated in front line CLL and I found this news story anecdote to be pretty exciting though you must be very careful with anecdotes and no formal reports are available.  Rituximab was evaluated in relapsed patients way back in the early 2000s with pretty modest single agent activity, though improved with higher dosing of the drug or greater frequency (another way of increasing the dose). 

You can bet you will hear a lot about "better versions of rituxan."  Look for head to head comparisons or results that are substantially different from prior series.  Rituxan was definitely a pioneer, but I fully expect we will be able to build a better treatment.  Here is a review published in ASH that goes over a lot of the information above and describes some of the other strategies to improve upon rituxan.