Monday, September 30, 2013

What is the value of antibody engineering in immunotherapy?

We at the Future of Biopharma blog recently had some time to sit down and speak with speakers from the Antibody Engineering and Therapeutics event. Today speaker Dr. Holbrook Kohrt, Associate Professor in the Department of Medicine in the Division of Oncology at Stanford University shares with us what he thinks the value of antibbdy engineering in immunotherapy is.
I actually think that antibody engineering is critical in the area of immunotherapy because of the interaction of a novel antibody that we are engineering today and applying for patients with cancer. 
What we’ve identified over the past 20 years, since the initial development of Rituximab, is an antibody that targets CD20 on the surface of non-Hodgkin’s lymphoma. Now, this antibody – Rituximab – was put into Phase I testing in 1994, FDA approved in 1997 and today is approximately an $8 million worldwide market in immunotherapy and induces responses anywhere between 60 and 90% of non-Hodgkin’s lymphoma patients and has been demonstrated to improve survival. 
Since the development of Rituximab, there have been multiple other antibodies developed, such as Trastuzumab, which targets HER2 on the surface of breast cancer, as well as Cetuximab, which targets EGFR on the surface of head and neck, as well as in colorectal and potentially in lung and other tumor types. 
Unfortunately, these monoclonal antibodies have failed to be the magic bullet that we all once hoped. So today the major additional effort is trying to identify how we can improve the efficacy of these monoclonal antibodies and thus the importance of antibody engineering.

For a long period of time we have considered antibody engineering really just as enhancing a single monoclonal antibody to improve its efficacy. But what I argue is that actually there is an alternative paradigm changing approach by antibody engineering to two targets simultaneously. Now this may sound similar to biospecifics or diabodies. But in fact, what I’m referring to is targeting one target on the tumor itself and a second target on a completely different cell type, specifically on an infector cell within the immune system. 
So, how do monoclonal antibodies work? Well, the majority monoclonal antibodies, such as Rituximab, work by ADCC – Antibody Dependent Cell-Mediated Cytotoxicity. In this process, a monoclonal antibody binds to the surface of the cell of interest, such as the lymphoma cell or breast cancer cell or the head and neck cancer cell. Once that first antibody binds, the Fc portion of that antibody recruits and binds to parts of the immune system, specifically natural killer cells or any cells bearing an Fc receptor. Now the affinity of that interaction is very important. So, if we can improve the first monoclonal antibody by making that affinity even higher, that’s one success. But the second success really comes by targeting the immune system. How can we do that? When these cells – the natural killer cells – bind to the Fc portion of a monoclonal antibody, that interaction triggers stimulation of them. That stimulation helps regulate things on their cell surface.

For the rest of Dr. Holbrook's answer, download the full podcast and PDF 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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