Project ID iCASE2024_01_CM-HD

ThemeCM-HD

Co Supervisor 1A Faculty of Life Sciences & Medicine, School of Cancer & Pharmaceutical Sciences, Comprehensive Cancer CentreWebsite

Co Supervisor 1B Faculty of Life Sciences & Medicine, School of Basic & Medical Biosciences, Randall Centre for Cell & Molecular BiophysicsWebsite

Additional Supervisor Dr Daniel Spencer

Partner Ludger Ltd

Engineering, characterisation and glycoprofiling of IgE antibodies for cancer immunotherapy

Half of patients with melanoma, the most lethal skin cancer, and a large proportion of patients with aggressive breast cancers such as the triple negative subtypes, do not respond to currently-available antibody immunotherapies. Existing anti-cancer antibody-based therapies are largely-focused on IgG-class antibodies. However, several features of IgG, including low Fc-receptor affinity, inhibitory Fc-receptors downregulating functional signalling, and poor tissue retention, can limit therapeutic response. IgE, the predominant antibody in allergic responses, is emerging as a promising novel anti-cancer therapeutic modality in the field of AllergoOncology. A growing repertoire of pre-clinical studies demonstrate the potential of anti-tumour IgE antibodies to restrict tumour growth and epidemiological studies highlight roles of IgE in tumour immunosurveillance. We have successfully completed a Phase 1 clinical trial of MOv18 IgE, the first-in-class IgE monoclonal antibody for cancer therapy. IgE is a highly-glycosylated antibody, however, there is insufficient understanding of the interplay between glycosylation and anti-tumour function. We have established a platform to generate and characterise IgE antibodies, including those with altered glycan profiles and showed that sialic acid influences the ability of IgE to mediate downstream signalling on immune cells. This project will identify optimal glycoengineered IgEs for cancer immunotherapy. In year 1, we will generate and characterise IgEs and glycovariant forms recognising melanoma-associated and breast cancer-associated antigens. In year 2, we will compare the functional attributes of paired glycoengineered and native IgEs in several in vitro assays. Years 3 and 4 will entail in vivo studies of selected IgE glycoforms in cancer models and tumour organoid models. The study will establish the impact of glycan structures on anti-tumour functions, and the importance of evaluating the glycan profiles of IgE candidates for cancer therapy. Ultimately, selection of optimal IgE glycoforms may lead to new treatment options for patients who do not presently benefit from established immunotherapies.

Third Supervisor: Prof Sophia Karagiannis

Representative Publications

Co-1A
1. Safety and anti-tumour activity of the IgE antibody MOv18 in patients with advanced solid tumours: a phase 1 trial’
Spicer J, Basu B, Montes A, Banerji U, Kristeleit R, Miller R, Veal G, Corrigan C, Till S, Figini M, Canevari S, Barton C, Jones P, Mellor S, Carroll S, Selkirk C, Nintos G, Kwatra V, Funingana I, Doherty G, Gould H, Pellizzari G, Nakamura M, Ilieva K, Khiabany A, Stavraka C, Chauhan J, Gillett C, Pinder P, Bax H, Josephs D & Karagiannis S
Nature Communications (2023) doi: 10.1038/s41467-023-39679-9
2. Intra-tumoral pan-ErbB targeted CAR-T for head and neck squamous cell carcinoma: interim analysis of the T4 immunotherapy study’
Sophie Papa S, Adami A, Metoudi M, Beatson R, George M, Achkova D, Williams E, Arif S, Reid F, Elstad M, Beckley-Hoelscher N, Douri A, Delord M, Lyne M, Shivapatham D, Fisher C, Hope A, Gooljar S, Mitra A, Gomm L, Morton C, Henley-Smith R, Thavaraj S, Santambrogio A, Andoniadou C, Allen S, Gibson V, Cook G, Parente-Pereira A, Davies D, Farzaneh F, Schurich A, Guerrero-Urbano T, Jeannon J, Spicer J & Maher J
Journal for ImmunoTherapy of Cancer (2023) doi: 10.1136/jitc-2023-007162
3. Safety, anti-tumor activity and T-cell responses in a dose-ranging phase 1 study of the oncolytic peptide LTX-315 in patients with solid tumors’
Spicer J, Marabelle A, Baurain J, Jebsen N, Jøssang D, Awada A, Kristeleit R, Loirat D, Lazaridis G, Jungels C, Brunsvig P, Nicholaisen B, Saunders A, Patel H, Galon J, Hermitte F; Camilio K, Mauseth B, Sundvold V, Sveinbjørnsson B & Rekdal Ø
Clinical Cancer Research (2021) doi: 10.1158/1078-0432.CCR-20-3435

Co-1B
1. J.M. McDonnell, B. Dhaliwal, B.J. Sutton and H.J. Gould (2023) IgE, IgE Receptors and Anti-IgE Biologics: Protein Structures and Mechanisms of Action. Annual Review of Immunology 41:255-275. doi: 10.1146/annurev-immunol-061020-053712.
2. A.M. Davies, R.L. Beavil, M. Barbolov, B.S. Sandhar, H.J. Gould, A.J. Beavil, B.J. Sutton and J.M. McDonnell (2023) Crystal structures of the human IgD Fab reveal insights into CH1 domain diversity. Mol Immunol 159:28-37. doi: 10.1016/ j.molimm.2023.05.006.x
3. R.M. Hoffmann, S. Mele, A. Cheung, D. Larcombe-Young, G. Bucaite, E. Sachouli, I. Zlatareva, H.O.J. Morad, R. Marlow, J.M. McDonnell, M. Figini, K.E. Lacy, A.J.N. Tutt, J.F. Spicer, D.E. Thurston, S.N. Karagiannis and S. Crescioli (2020) Rapid Conjugation of Antibodies to Toxins to Select Candidates for the Development of Anticancer Antibody-Drug Conjugates (ADCs). Scientific Reports 10(1):8869. doi: 10.1038/s41598-020-65860-x.

3rd Superviosr
1. Chauhan J, Grandits M, Palhares LCGF, Mele S, Nakamura M, López-Abente J, Crescioli S, Laddach R, Romero-Clavijo P, Cheung A, Stavraka C, Chenoweth AM, Sow HS, Chiaruttini G, Gilbert AE, Dodev T, Koers A, Pellizzari G, Ilieva KM, Man F, Ali N, Hobbs C, Lombardi S, Lionarons DA, Gould HJ, Beavil AJ, Geh JLC, MacKenzie Ross AD, Healy C, Calonje E, Downward J, Nestle FO, Tsoka S, Josephs DH, Blower PJ, Karagiannis P, Lacy KE, Spicer J, Karagiannis SN*, Bax HJ. Anti-cancer pro-inflammatory effects of an IgE antibody targeting the melanoma-associated antigen chondroitin sulfate proteoglycan 4. Nat Commun. 2023 14(1):2192; doi: 10.1038/s41467-023-37811-3.
2. McCraw AJ, Gardner RA, Davies AM, Spencer DIR, Grandits M, Wagner GK, McDonnell JM, Karagiannis SN, Chenoweth A, Crescioli S. Generation and Characterization of Native and Sialic Acid-Deficient IgE. Int J Mol Sci. 2022 23(21):13455. doi: 10.3390/ijms232113455.
3. Pellizzari G, Martinez O, Crescioli S, Page R, Di Meo A, Mele S, Chiaruttini G, Hoinka J, Batruch I, Prassas I, Grandits M, López-Abente J, Bugallo-Blanco E, Ward M, Bax HJ, French E, Cheung A, Lombardi S, Figini M, Lacy KE, Diamandis EP, Josephs DH, Spicer J, Papa S, Karagiannis SN*. Immunotherapy using IgE or CAR T cells for cancers expressing the tumor antigen SLC3A2. J Immunother Cancer. 2021 9(6):e002140. doi: 10.1136/jitc-2020-002140.