Aaron Ring, MD, PhD
Research & Publications
The overarching objective of our research is to understand and manipulate the communication circuitry of the immune system using precision immunopharmacology and systems immunology. Specifically, we use directed evolution to create new pharmacologic tools and therapeutics against key immune receptors. Additionally, we have begun to re-purpose the same directed evolution technologies for systems immunology; for example, to discover and profile functional humoral responses that mediate and mitigate disease and to detect novel transkingom interactions between our microbiota and the human exoproteome.
Extensive Research Description
Our research programs involve pharmacologic dissection of immune signaling pathways as well as developing new tools for systems immunology research.
Engineering cytokines for cancer immunotherapy with directed evolution. Cytokines were the first drugs that proved the immune system could be an ally against cancer, but they have been limited in their therapeutic use due to their biological pleiotropism (having multiple inputs and outputs). We are using directed evolution to create new immune cytokines with precisely defined activities. These “designer” proteins enable fine mechanistic dissection of immune signaling pathways and also offer pharmacologic tools for therapeutic development. As a recent example, we developed a version of IL-18 that is impervious to a tumor-produced “jamming signal” called IL-18BP. We found engineered IL-18 has dramatically increased anti-tumor efficacy in multiple mouse cancer models (Zhou et a., Nature, 2020) and the molecule is now being developed for clinical use, with clinical trials expected to start in 2021.
Mapping the interactome between microbes and the host exoproteome. We are collaborating with Noah’s Palm laboratory to explore host:microbe interactions in commensal and pathobiont microbes using a novel technology we developed called BASEHIT. This platform allows us to identify potential interactions between bacteria and >3,000 extracellular and secreted human proteins (the “exoproteome”). These novel interactions provide new insights into how our microbiota influence our health and disease.
Discovering novel autoantibody responses in autoimmune disease and cancer. Autoantibodies are classically associated with contributing to autoimmune disease, however, there is growing recognition that some autoantibody responses have beneficial effects. For instance, cancer patients that make antibodies against tumor proteins have better outcomes. Similarly, autoimmune disease patients that make immunosuppressive anti-cytokine antibodies have less severe disease. Discovering disease-ameliorating antibody responses can thus give insights into potential new therapeutic targets and potentially drugs themselves. To discover functional autoantibody responses, we developed a technology called REAP (Rapid Exoproteome Antigen Profiling) that allows for the comprehensive identification of autoantibody responses to the exoproteome with just a small volume of serum/plasma and in high throughput. We are now applying REAP to numerous diseases, including patients with COVID-19, cancer patients treated with immunotherapy, and patients with systemic lupus erythematosus and other autoimmune conditions.
Comprehensive discovery of ‘nanobodies’ to extracellular and secreted proteins. Single domain antibodies (‘nanobodies’) are powerful research tools and an emerging class of therapeutics. We have created a pipeline to discover and validate nanobodies against thousands of extracellular antigens. We are using the discovered nanobodies as probes for single-cell proteomics and also as open-source pharmacologic tools.
Immune System; Neoplasms; Systems Biology; Drug Discovery; Immunomodulation
- IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapyZhou T, Damsky W, Weizman OE, McGeary MK, Hartmann KP, Rosen CE, Fischer S, Jackson R, Flavell RA, Wang J, Sanmamed MF, Bosenberg MW, Ring AM. IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapy Nature 2020, 583: 609-614. PMID: 32581358, PMCID: PMC7381364, DOI: 10.1038/s41586-020-2422-6.
- Hematopoietic stem cell transplantation in immunocompetent hosts without radiation or chemotherapyChhabra A, Ring AM, Weiskopf K, Schnorr PJ, Gordon S, Le AC, Kwon HS, Ring NG, Volkmer J, Ho PY, Tseng S, Weissman IL, Shizuru JA. Hematopoietic stem cell transplantation in immunocompetent hosts without radiation or chemotherapy Science Translational Medicine 2016, 8: 351ra105. PMID: 27510901, PMCID: PMC6668627, DOI: 10.1126/scitranslmed.aae0501.
- Engineering high-affinity PD-1 variants for optimized immunotherapy and immuno-PET imagingMaute RL, Gordon SR, Mayer AT, McCracken MN, Natarajan A, Ring NG, Kimura R, Tsai JM, Manglik A, Kruse AC, Gambhir SS, Weissman IL, Ring AM. Engineering high-affinity PD-1 variants for optimized immunotherapy and immuno-PET imaging Proceedings Of The National Academy Of Sciences Of The United States Of America 2015, 112: e6506-e6514. PMID: 26604307, PMCID: PMC4664306, DOI: 10.1073/pnas.1519623112.
- Interleukin-2 Activity Can Be Fine Tuned with Engineered Receptor Signaling ClampsMitra S, Ring AM, Amarnath S, Spangler JB, Li P, Ju W, Fischer S, Oh J, Spolski R, Weiskopf K, Kohrt H, Foley JE, Rajagopalan S, Long EO, Fowler DH, Waldmann TA, Garcia KC, Leonard WJ. Interleukin-2 Activity Can Be Fine Tuned with Engineered Receptor Signaling Clamps Immunity 2015, 42: 826-838. PMID: 25992859, PMCID: PMC4560365, DOI: 10.1016/j.immuni.2015.04.018.
- Activation and allosteric modulation of a muscarinic acetylcholine receptorKruse AC, Ring AM, Manglik A, Hu J, Hu K, Eitel K, Hübner H, Pardon E, Valant C, Sexton PM, Christopoulos A, Felder CC, Gmeiner P, Steyaert J, Weis WI, Garcia KC, Wess J, Kobilka BK. Activation and allosteric modulation of a muscarinic acetylcholine receptor Nature 2013, 504: 101-106. PMID: 24256733, PMCID: PMC4020789, DOI: 10.1038/nature12735.
- Adrenaline-activated structure of β2-adrenoceptor stabilized by an engineered nanobodyRing AM, Manglik A, Kruse AC, Enos MD, Weis WI, Garcia KC, Kobilka BK. Adrenaline-activated structure of β2-adrenoceptor stabilized by an engineered nanobody Nature 2013, 502: 575-579. PMID: 24056936, PMCID: PMC3822040, DOI: 10.1038/nature12572.
- Engineered SIRPα Variants as Immunotherapeutic Adjuvants to Anticancer AntibodiesWeiskopf K, Ring AM, Ho CC, Volkmer JP, Levin AM, Volkmer AK, Özkan E, Fernhoff NB, van de Rijn M, Weissman IL, Garcia KC. Engineered SIRPα Variants as Immunotherapeutic Adjuvants to Anticancer Antibodies Science 2013, 341: 88-91. PMID: 23722425, PMCID: PMC3810306, DOI: 10.1126/science.1238856.
- Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15Ring AM, Lin JX, Feng D, Mitra S, Rickert M, Bowman GR, Pande VS, Li P, Moraga I, Spolski R, Özkan E, Leonard WJ, Garcia KC. Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15 Nature Immunology 2012, 13: 1187-1195. PMID: 23104097, PMCID: PMC3501574, DOI: 10.1038/ni.2449.
- Exploiting a natural conformational switch to engineer an interleukin-2 ‘superkine’Levin AM, Bates DL, Ring AM, Krieg C, Lin JT, Su L, Moraga I, Raeber ME, Bowman GR, Novick P, Pande VS, Fathman CG, Boyman O, Garcia KC. Exploiting a natural conformational switch to engineer an interleukin-2 ‘superkine’ Nature 2012, 484: 529-533. PMID: 22446627, PMCID: PMC3338870, DOI: 10.1038/nature10975.