Katharine M. Wright
The emergence of immunotherapy as an important tool in the fight against cancer takes advantage of the exquisite specificity of antibodies. Targets, however, are limited to those on the cell surface, while most driver mutations occur in the genes encoding intracellular proteins. To overcome this limitation, antibodies can be engineered to target peptides derived from mutant proteins that are presented on the cell surface by major histocompatibility complex class I [pMHC-I]. My studies conducted in the Gabelli lab elucidated the structural basis for antibody recognition to MHC-presented neoantigens to garner potent “off the shelf” therapeutics. Specifically, we have designed and developed two antibody bispecifics, called H2 and V2, that target a peptide derived from the tumor suppressor gene TP53 R175H mutation and the oncogene KRAS G12V mutation, respectively. Binding kinetics experiments revealed the two bispecifics bind their respective mutant pMHC with different kinetics, suggesting different modes of binding. The structure of the p53R175H-pMHC bound to the H2-Fab fragment showed that the H2 antibody formed a cage-like configuration around the p53R175H peptide, trapping the mutant histidine [His175] and the adjacent arginine [Arg174] residues in a stable interaction, providing the structural basis for the specificity. In contrast, the structure of the KRASG12V-pMHC bound to the V2-IgG showed a very hydrophobic interaction and a conformational change upon binding, highlighting the specificity. Notably, the two antibody fragments, in a bispecific format, induced a potent and specific T cell response. Our detailed structural understanding of the mechanisms of specificity allows for the development of more effective therapeutics. By exploiting the MHC-I presentation of neoantigens, we have achieved the first step toward a precision off-the-shelf medicine therapeutic that selectively targets mutated driver genes.
Questions & Answers
Why did you choose Johns Hopkins for your work? I chose The Johns Hopkins University because the institution is the home of novel discoveries and many firsts. For example, Hopkins was one of the first universities to admit women into medical school and higher education programs, an essential principle for myself as a woman Ph.D. in science. Along those lines, I wanted to have mentors that were women who hold high level titles as I proceeded in my scientific career. Therefore, joining Dr. Sandra Gabelli’s lab allowed me to have that opportunity as well as expand my structural biology knowledge, learning both X-ray crystallography and cryo- EM. What does receiving this award mean to you personally and professionally? Do you have any connection with the particular award you received? I am very honored to receive the Paul Ehrlich Award. For me personally, it provides me with drive to continue research in fields of high impact and need. As a pioneer in the field of immunology, Paul Ehrlich popularized the concept of a “magic bullet,” which is a drug specifically targeting a particular pathogen without affecting normal cells. This idea of a target-specific approach is fundamental and the basis for my work and research discovery. What contributed to your project’s success? (Special skills, interests, opportunities, guidance, etc.) The talented, hard-working and dedicated people that I have been lucky to work with on this project — specifically, the mentorship I gained from Dr. Gabelli was a driving force in critical moments. She was encouraging, patient and supportive in all aspects of the project. Also, I have had the pleasure to work in a collaborative, multidisciplinary and hypothesis driven environment with the Kinzler-Vogelstein-Zhou lab, which has allowed me to learn drug discovery for immuno-oncology. What thoughts do you have about Young Investigators’ Day itself, as a celebration of the roles students and fellows play in research at Hopkins? Young Investigators’ Day is a community day during which JHU celebrates its trainees’ achievements. Events such as this one make trainees feel appreciated by JHU. What has been your best/most memorable experience while at Hopkins? The most memorable moment was when the paper on targeting a p53 neoantigen, of which I am co-first author, was accepted into the journal Science for publication! This achievement highlighted the true teamwork, diligence and perseverance that is needed in scientific research. What are your plans over the next year or so? Graduating, looking for faculty positions, etc.? In the next year, I plan to publish the work presented here on the structural determinants for targeting the KRAS G12V mutation. During that time, I will also be taking the next steps to continue my career in structural biology in industry. Tell me something interesting about yourself that makes you unique. Do you have any special hobbies, interests or life experiences? I love to kickbox, especially early in the morning before work. For an hour, I only think about the exercise, nothing else, and this allows me to get ready for my day!