VBS Team Science: Activating Antibodies Against Tumors

The National Cancer Institute defines Team Science as, “A collaborative effort to address a scientific challenge that leverages the strengths and expertise of professionals.” The Department of Veterinary and Biomedical Sciences (VBS) recognizes the benefits of team science, and fosters an environment that allows researchers to pursue transdisciplinary projects. This provides access to more resources, exposure to diverse types of investments, and an ability to engage multiple stakeholders. Team science approaches lead to greater scientific impact, innovation, productivity, and reach compared to work by single investigators.

Two VBS Principal Investigators, Professor Bruce Walcheck and Professor Jianming (Jimmy) Wu have been collaborating on several important projects for the past decade. Their combined scientific expertise has led to rewarding outcomes such as publications, grants, patents, and research contracts with the pharmaceutical industry. They kindly agreed to answer a few questions for this interview.

How did you begin working together on your immune cancer research projects?

Bruce: Our collaborations began with Jimmy’s suggestion to examine whether ADAM17 might cleave CD16. CD16 is a receptor on leukocytes that binds to antibodies, serving as a key mechanism by which leukocytes are activated to perform their various protective functions. ADAM17 is a protease also expressed by leukocytes that regulates receptor expression levels and leukocyte activation. I remember that at the time we were very focused on studying other roles of ADAM17 and didn’t know much about CD16, so it wasn’t high on my priority list. However, my postdoc performed experiments to test Jimmy's hypothesis, and we found that CD16 was clearly cleaved by ADAM17. Currently, Fate Therapeutics is testing one of our engineered CD16 receptors in human clinical trials. Looking back, I’m grateful for Jimmy’s ideas and my postdoc’s interest in trying some new experiments. 

Jimmy: The collaboration started 15 years ago when I moved from the University of Alabama at Birmingham to Minnesota and my lab was next to Bruce’s. It was very convenient for me to go to next door to seek help while I was setting up my own lab at the time. I was also discussing my research projects during my visits. Bruce’s lab had been working on ADAM17 (a metalloprotease) that cleaves a number of immune molecules for the regulation of immune responses, whereas my research has been focused on genetic effects of human immunoglobuklin G (IgG) Fc receptors on immune responses and autoimmune diseases.  I was aware that the IgG Fc receptor CD16 on immune cells could be down-regulated or cleaved by an unknown protease, and suggested to Bruce's postdoctoral fellow that he examine whether ADAM17 could cleave CD16 with the reagents from my lab.  Our collaboration resulted in the delineation of ADAM17 as the enzyme to cleave CD16 family IgG Fc receptors (CD16A and CD16B) that play crucial roles in immune responses and are extensively expressed on immune cells, including neutrophils, monocytes, NK cells, and subsets of T cells. We subsequently mapped the cleavage sites on CD16A and CD16B, laying the foundation for engineered CD16 molecules that could resist ADAM17 cleavage and be useful in immunotherapy.

What are some of your notable successes (e.g. patents, etc.)

Bruce and Jimmy: Publications; NIH grants; currently two patents and working on a third; sponsored projects with Fate Therapeutics,  a pharmaceutical company; CVM and Cancer Center grants, a Regenerative Medicine grant, and a Minnesota Ovarian Cancer Alliance SEED grant.

What are your current projects?

Bruce: In addition to generating a non-ADAM17-cleavable CD16  receptor currently being tested in clinical trials, we generated a CD64/CD16 fusion receptor as a next-generation receptor for expression in engineered natural killer cells or T cells to be used as an immunotherapy for cancer, autoimmunity, or infectious disease. CD64 binds to IgG antibodies with much higher affinity than CD16 and this has key advantages for enhancing the function of immune cells called natural killer (NK) cells. We basically combined CD64 and CD16 together, keeping the most important and unique features of each one. With our understanding of human CD16 and CD64 and how these can be used to enhance the function of human immune cells, Jimmy and I were the first to generate antibodies to these receptors in dogs and have characterized immune cell populations that express them. We hope this might lead to novel cancer immunotherapies for dogs. However, a major challenge is obtaining significant grant funding in this area, which is more difficult than for human immunotherapies. 

Jimmy: We would like to get final approval of our CD64/16 patent (International Application Number PCT/US2018/057689. US Patent Application # 62/577,42). In addition, we are developing a new research direction with recombinant immunoglobulin Fc receptors for human immunotherapies. We aim to generate high affinity, recombinant human Ig receptors that can irreversibly bind monoclonal antibodies specific for tumor or pathogen antigens. These molecules could potently activate specific immune cell types including natural killer cells and T cells for immunotherapy of human cancer and infectious diseases. We have set up a platform to produce many classes of recombinant human monoclonal antibodies for lab experiments.  The high affinity recombinant Fc receptors are intended to serve as a universal antigen receptor combination with specific monoclonal antibodies. We will submit a new grant application once we obtain the necessary experimental data. 

What are your thoughts about the value of collaboration and bringing different perspectives to a scientific problem?

Bruce: Collaboration is essential for biomedical research to tap into other areas of expertise, perspectives, and strategies. Thanks to my collaborations with Jimmy, my research has gone in new and unexpected directions. 

Jimmy: I wasn't familiar with ADAM17 until I collaborated with Bruce’s lab. Collaboration is essential to evolve and expand our research into translational medicine and the clinic.

What do you like to do in your free time?

Bruce: Doing research may not leave much free time because there is always something that needs to be done or new directions to go. I have many hobbies and interests that are necessary to help me escape the aspects of research that can be very frustrating - such as grant rejections and manuscript revisions.

Jimmy: I like gardening and growing vegetables in my free time. I enjoy watching college football and basketball games.