Monday, October 7, 2013

Antibody Engineering: A Deeper Look into CD137

Last week, Antibody Engineering and Therapeutics speaker Dr. Holbrook Khort discussed what antibody engineering is and how monoclonal antibodies work. 

This week, he takes a deeper look at the CD137.

One of the things that we have identified in the laboratory that becomes self-regulated is known as “CD137”. This is also known as 4-1BB. CD137 is a member of the tumor necrosis factor receptor superfamily, specifically Knfr9. When CD137 trimorizes on the surface of a natural killer cell, this induces activation of the cell. That activation process stimulates it even further. That stimulation leads to downstream calciumoxide and other signaling aspects, as well as cell survival. But the most important part is that extra calcium influx leads to enhanced cytotoxicity, better release of granules, better release of interferon gamma and potentially better affector function. What this is able to do is actually increase the ability of that NK cell to kill its target cell of interest. 
What we have shown in a series of different pre-clinical models is that the combination of targeting CD137 with an agonistic antibody causes trimorization of it on the surface of the cell. In combination with an antibody targeting, say, lymphoma such as Rituxan, is indeed synergistic on top of either of these antibodies alone. Very interestingly, targeting CD137 as a monotherapy has little to no activity. It also has the advantage of almost no toxicity. When combined with Rituxan it has striking activity without any signal of enhanced toxicity in the mouse models. 
Now when we look at Trastuzumab, we have shown the same thing and we are currently in the process of looking at a Cetuximab model, as well. What is important is that we have demonstrated that even in Trastuzumab-resistant tumor cell lines, the combination of Trastuzumab and CD137 actually has enhanced activity. This means that not only could we increase the responses of breast cancer patients today that express HER2, but as patients become resistant over time, we would still have a therapy reserved for them.
Going forward, where are we going to be in the future? At present, we are conducting four clinical trials for CD137, two that are focused as monotherapy and two that are focused in combination with Rituxan. This study is currently ongoing and being run by Bristol-Myers Squibb and also by Pfizer. Hopefully by the end of the year we will also have a clinical trial that is targeting not only the lymphoma population, but also the breast cancer population with Trastuzumab, as well as a head and neck and colorectal population with Cetuximab.

The last important point is that we believe these therapies really apply to patients who are otherwise previously resistant or potentially non-responders to these monoclonal antibodies. We have shown in the Trastuzumab models that patients who indeed have a KRAS mutation and otherwise would not respond to Rituximab will likely respond to the therapy. So, we do indeed hope that the next generation level of the antibody engineering is going to go well beyond just mutating the xB portion or increasing binding affinity and indeed will actually be approaching patients by targeting two different parts of their tumor and their immune system at the same time.

To hear the full podcast and read the full transcript, download it here.

Dr. Kohrt will be presenting Stimulation of Natural Killer Cells with an Anti-CD137 Antibody Enhances the Efficacy of Trastuzumab, Cetuximab, and Rituximab in HER2-expressing Breast Cancer, EGFR+ Head and Neck Cancer, and CD20+ Lymphoma on Wednesday, December 11 at the Antibody Engineering and Therapeutics Event.  For more information on his session and the rest of the program, download the agenda.  If you'd like to join us, as a reader of this blog, when you register to join us and mention priority code XD13172BLOGJP, you can save 20% off the standard rate!

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