Peptides to regulate macrophages in cancer, autoimmunity, and infectious disease
Designing technologies and drugs to direct macrophages to block or initiate inflammation
Macrophages have a unique plasticity. These phagocytic cells of the innate immune response dynamically and rapidly switch between promoting and suppressing immune reactions. They are often the first cells encountered by drugs and other therapies. The activities of macrophages are therefore a major influence on a patient’s response to treatment such as immunotherapy.
The EDIT lab (for Engineering and Designing Immunotherapies), led by Dr. Heather Gustafson, is developing novel technology platforms focused on macrophages and their activities, particularly their release of cytokines. These short-lived small proteins direct the immune response, for example toward inflammation or anti-inflammation, by activating signalling cascades that alter gene expression in target cells. One area of EDIT lab research is identifying targets and developing peptide drugs to regulate immune responses by controlling the production and release of cytokines from macrophages.
Dr. Gustafson has expertise in engineering peptides to regulate macrophages. She was part of a team that developed peptides to activate NLRP3 inflammasomes. Inflammasomes are supermolecular organizing centers (SMOCs), which are intracellular complexes that coordinate cellular signaling within the innate immune system downstream of pattern-recognition receptors (PRRs). PRR detection of pathogens or cell damage activates various SMOC formation (e.g. myddosome, inflammasome, necrosome). These large signalosomes coordinate intracellular adapters, signaling enzymes and their substrates, facilitating proximity driven biochemistry. These coordination centers can induce pro-inflammatory cytokine production (with the type and level of cytokine production depending on the type of SMOC(s) activated), and may in some cases induce inflammatory cell death (e.g. necroptosis or pyroptosis). Controlled activation of innate immune SMOCs near tumors could drive various cytokine programs or induce inflammatory cell death. One could imagine that this activity could act as a “bomb” overcoming immune-suppressive activity of cancer cells.
The EDIT lab is now engineering peptides that trigger the assembly and activity of a number of SMOCs in macrophages. Since macrophages direct immune responses in both pro- and anti-inflammatory directions, the goal is to use peptide drugs to promote different cytokine programs that can direct inflammation against infectious agents, tumors or dampen inflammation in detrimental conditions such as autoimmunity.
Projects in the EDIT lab are also identifying cytokine profiles and features of macrophages that are associated with favorable or poor responses to immunotherapy. The results will help identify new macrophage-focused drug targets. The team is developing a mouse model that can be used to test the effects of candidate peptide drugs to manipulate macrophages. These drugs could increase the effectiveness of immunotherapy, prevent severe drug reactions, and treat diseases in which an overreactive cytokine storm is implicated in poor outcomes, including influenza and COVID-19.
Dr. Gustafson also has expertise in drug delivery systems. She is interested in partnerships that use the EDIT lab’s knowledge and technical expertise to advance macrophage-focused peptide drugs to prevent or treat diseases and improve immunotherapy outcomes.
Stage of Development
- Pre-clinical in vitro
- Pre-clinical in vivo
- Sponsored research agreement
- Collaborative research opportunity
- Consultation agreement
- Gustafson HH, Pun SH. Instructing macrophages to fight cancer. Nat Biomed Eng 2018. 2(8):559-561. doi: 10.1038/s41551-018-0276-0.
- Gustafson HH, Olshefsky A, Sylvestre M, Sellers DL, Pun SH. Current state of in vivo panning technologies: Designing specificity and affinity into the future of drug targeting. Adv Drug Deliv Rev 2018. 130:39-49. doi: 10.1016/j.addr.2018.06.015.
- Ngambenjawong C, Gustafson HH, Pun SH. Progress in tumor-associated macrophage (TAM)-targeted therapeutics. Adv Drug Deliv Rev 2017. 114:206-221. doi: 10.1016/j.addr.2017.04.010.
- Ngambenjawong C, Gustafson HH, Pineda JM, Kacherovsky NA, Cieslewicz M, Pun SH. Serum stability and affinity optimization of an M2 macrophage-targeting peptide (M2pep). Theranostics 2016. 6(9):1403-14. doi: 10.7150/thno.15394.
- Gustafson HH, Holt-Casper D, Grainger DW, Ghandehari H. Nanoparticle Uptake: The Phagocyte Problem. Nano Today 2015 10(4):487-510. doi: 10.1016/j.nantod.2015.06.006
- Herd H, Daum N, Jones AT, Huwer H, Ghandehari H, Lehr CM. Nanoparticle geometry and surface orientation influence mode of cellular uptake. ACS Nano 2013. 7 (3), 1961-1973 doi: 10.1021/nn304439f
- Moos PJ, Honeggar M, Malugin A, Herd H, Thiagarajan G, Ghandehari H. Transcriptional responses of human aortic endothelial cells to nanoconstructs used in biomedical applications. Mol Pharm 2013. 10 (8): 3242-3252 doi: 10.1021/mp400285u
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