A/Prof Melissa Call, Lab Head | WEHI Researcher Profile

Q: Tuning CAR T-cell potency with de novo designed receptor transmembrane domains

With collaborator Sarel Fleishman (Weizmann Institute of Science, Israel), we have developed and validated a panel of de novo designed transmembrane domains (TMDs) that form stable and specific monomeric, dimeric, trimeric and tetrameric structures in cell membranes. We used these to enforce the corresponding oligomeric states in second-generation chimeric antigen receptors (CARs) against the solid tumour antigen HER2 and showed that both tumour control and cytokine production scaled in direct proportion to the designed oligomeric structure of the TMD (see eLife 2022). Ongoing work in this program is focused on (1) expanding our panel of available TMD sequences and structures, (2) testing the clinical relevance of these new tools for optimising the safety/efficacy profiles of cellular immunotherapies in specific cancer contexts and (3) developing even more sophisticated applications for these sequences in the cellular immunotherapy space. Project resources:'Goldilocks' treatment window could lead to cancer therapy without harmful side-effects [https://www.wehi.edu.au/news/goldilocks-treatment-window-could-lead-cancer-therapy-without-harmful-side-effects]

Q: Understanding the mechanisms of type-I cytokine receptor activation

Homodimeric type I cytokine receptors for growth hormone, erythropoietin and thrombopoietin (GHR, EpoR, TpoR) control processes essential to human health such as tissue growth, regeneration and blood cell production. Impaired activation and/or signalling of these receptors can lead to various pathological conditions, including blood pathologies, cancers, developmental and metabolic disorders. GHR, EpoR, TpoR transmit signals by forming specific structures in their transmembrane domains (TM), though the identities of active and inactive orientations are not well understood. Our laboratory utilizes deep mutational scanning methods coupled to next-generation sequencing to evaluate how a large number of mutations in these receptors’ TM and flanking regions affects their function. Project resources:Genetic cause of blood disease found [https://www.wehi.edu.au/news/genetic-drivers-myeloproliferative-diseases-revealed]

About

We have a particular focus on how the transmembrane domains of receptors contribute to the structure and function of immune-signalling complexes. These are not mere anchors for extracellular and intracellular domains, but provide a unique platform for molecular interactions and represent the only direct physical link between ligand-binding and signalling domains across the cell barrier.

To understand how receptors are activated and the interactions the make with other proteins we are using deep-mutational scanning to uncover mechanistic insights, such as which areas of the protein are susceptible to disease-causing mutations and how to these relate to the natural function of the receptor. A major focus in recent years has been the development (with computational protein design collaborators) and structural characterisation (by x-ray crystallography) of synthetic transmembrane domains as tools to control the structures and activities of engineered receptors such as chimeric antigen receptors for CAR T-cell immunotherapies.

During the pandemic we pivoted some of our research towards understanding how SARS-CoV-2 will respond to therapeutics targeting the viral proteases required for SARS-CoV-2 replication. Our research will predict viral escape mutants before they are observed in the clinic and provide deeper mechanistic insight into Mpro and PLpro function.

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Selected publications from A/Prof Melissa Call

M. Bader S, Calleja DJ, Devine SM, Kuchel NW, Lu BGC, Wu X, Birkinshaw RW, Bhandari R, Loi K, Volpe R, Khakham Y, Au AE, Blackmore TR, Mackiewicz L, Dayton M, Schaefer J, Scherer L, Stock AT, Cooney JP, Schoffer K, Maluenda A, Kleeman EA, Davidson KC, Allison CC, Ebert G, Chen G, Katneni K, Klemm TA, Nachbur U, Georgy SR, Czabotar PE, Hannan AJ, Putoczki TL, Tanzer M, Pellegrini M, Lechtenberg BC, Charman SA, Call MJ, Mitchell JP, Lowes KN, Lessene G, Doerflinger M, Komander D. A novel PLpro inhibitor improves outcomes in a pre-clinical model of long COVID. Nature Communications. 2025;16(1):10.1038/s41467-025-57905-4

Cater RJ, Ryan RM, Oakhill JS, Czabotar P, Murphy JM, Call MJ. Structure, function, surf, repeat: A week at Lorne Proteins 2024. Structure. 2024;32(11):10.1016/j.str.2024.10.007

Wu X, Go M, Nguyen JV, Kuchel NW, Lu BGC, Zeglinski K, Lowes KN, Calleja DJ, Mitchell JP, Lessene G, Komander D, Call ME, Call MJ. Mutational profiling of SARS-CoV-2 papain-like protease reveals requirements for function, structure, and drug escape. Nature Communications. 2024;15(1):10.1038/s41467-024-50566-9

Ramesh S, Go M, Call ME, Call MJ. Deep mutational scanning reveals transmembrane features governing surface expression of the B cell antigen receptor. Frontiers in Immunology. 2024;15:10.3389/fimmu.2024.1426795

Borger JG, Ng AP, Anderton H, Ashdown GW, Auld M, Blewitt ME, Brown DV, Call MJ, Collins P, Freytag S, Harrison LC, Hesping E, Hoysted J, Johnston A, McInneny A, Tang P, Whitehead L, Jex A, Naik SH. Artificial intelligence takes center stage: exploring the capabilities and implications of ChatGPT and other AI‐assisted technologies in scientific research and education. Immunology and Cell Biology. 2023;101(10):10.1111/imcb.12689

Chandler NJ, Davey AS, Elazar A, Weinstein JY, Nguyen JV, Trenker R, Cross RS, Jenkins MR, Call ME, Fleishman SJ, Call MJ. De novo -designed transmembrane domains tune chimeric antigen receptor function. Acta Crystallographica Section A: Foundations and advances. 2023;79(a2):10.1107/s2053273323086722

Abbott RC, Iliopoulos M, Watson KA, Arcucci V, Go M, Hughes‐Parry HE, Smith P, Call MJ, Cross RS, Jenkins MR. Human EGFRvIII chimeric antigen receptor T cells demonstrate favorable safety profile and curative responses in orthotopic glioblastoma. Clinical & Translational Immunology. 2023;12(3):10.1002/cti2.1440

Ramesh S, Park S, Im W, Call MJ, Call ME. T cell and B cell antigen receptors share a conserved core transmembrane structure. Proceedings of the National Academy of Sciences of the United States of America. 2022;119(48):10.1073/pnas.2208058119

Elazar A, Chandler NJ, Davey AS, Weinstein JY, Nguyen JV, Trenker R, Cross RS, Jenkins MR, Call MJ, Call ME, Fleishman SJ. De novo-designed transmembrane domains tune engineered receptor functions. eLife. 2022;11:10.7554/elife.75660

Calleja DJ, Kuchel N, Lu BGC, Birkinshaw RW, Klemm T, Doerflinger M, Cooney JP, Mackiewicz L, Au AE, Yap YQ, Blackmore TR, Katneni K, Crighton E, Newman J, Jarman KE, Call MJ, Lechtenberg BC, Czabotar PE, Pellegrini M, Charman SA, Lowes KN, Mitchell JP, Nachbur U, Lessene G, Komander D. Insights Into Drug Repurposing, as Well as Specificity and Compound Properties of Piperidine-Based SARS-CoV-2 PLpro Inhibitors. Frontiers in Chemistry. 2022;10:10.3389/fchem.2022.861209

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Lab research projects

Tuning CAR T-cell potency with de novo designed receptor transmembrane domains

Understanding the mechanisms of type-I cytokine receptor activation

Student research projects

Deep mutational scanning to characterise MLKL’s killer 4HB domain

Graduate Research Masters/Honours/Masters by Coursework/PhD

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Deep mutational scanning to characterise MLKL’s killer 4HB domain

Graduate Research Masters/Honours/Masters by Coursework/PhD

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A/Prof Melissa Call

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