Anti-cancer Pro-inflammatory Effects of an IgE Antibody Targeting the Melanoma-associated Antigen Chondroitin Sulfate Proteoglycan 4

Jitesh Chauhan; Melanie Grandits; Lais Cristina Gusmao Ferreira; Silvia Mele; Mano Nakamura; Jacobo Lopez-Abente Muroz; Silvia Crescioli; Roman Laddach; Pablo Romero Clavijo; Anthony Cheung; Chara Stavraka; Alicia Chenoweth; Heng Sheng Sow; Giulia Chiaruttini; Amy Gilbert; Tihomir Dodev; Alex Koers; Giulia Pellizzari; Kristina Ilieva; Francis Man; Niwa Ali; Carl Hobbs; Sara Lombardi; Daniël A. Lionarons; Hannah J. Gould; Andrew Beavil; Jenny L. C. Geh; Alastair D MacKenzie Ross; Ciaran Healy; Eduardo Calonje; Julian Downward; Frank Nestle; Sophia Tsoka; Debra Josephs; Philip Blower; Panagiotis Karagiannis; Katie E. Lacy; James Spicer; Sophia N Karagiannis; Heather Bax

doi:https://doi.org/10.1038/s41467-023-37811-3

Anti-cancer Pro-inflammatory Effects of an IgE Antibody Targeting the Melanoma-associated Antigen Chondroitin Sulfate Proteoglycan 4

Jitesh Chauhan, Melanie Grandits, Lais Cristina Gusmao Ferreira, Silvia Mele, Mano Nakamura, Jacobo Lopez-Abente Muroz, Silvia Crescioli, Roman Laddach, Pablo Romero Clavijo, Anthony Cheung, Chara Stavraka, Alicia Chenoweth, Heng Sheng Sow, Giulia Chiaruttini, Amy Gilbert, Tihomir Dodev, Alex Koers, Giulia Pellizzari, Kristina Ilieva, Francis ManNiwa Ali, Carl Hobbs, Sara Lombardi, Daniël A. Lionarons, Hannah J. Gould, Andrew Beavil, Jenny L. C. Geh, Alastair D MacKenzie Ross, Ciaran Healy, Eduardo Calonje, Julian Downward, Frank Nestle, Sophia Tsoka, Debra Josephs, Philip Blower, Panagiotis Karagiannis, Katie E. Lacy, James Spicer, Sophia N Karagiannis, Heather Bax

Research output: Contribution to journal › Article › peer-review

9 Downloads (Pure)

Abstract

Outcomes for half of patients with melanoma remain poor despite standard-of-care checkpoint inhibitor therapies. The prevalence of the melanoma-associated antigen chondroitin sulfate proteoglycan 4 (CSPG4) expression is ~70%, therefore effective immunotherapies directed at CSPG4 could benefit many patients. Since IgE exerts potent immune-activating functions in tissues, we engineer a monoclonal IgE antibody with human constant domains recognizing CSPG4 to target melanoma. CSPG4 IgE binds to human melanomas including metastases, mediates tumoricidal antibody-dependent cellular cytotoxicity and stimulates human IgE Fc-receptor-expressing monocytes towards pro-inflammatory phenotypes. IgE demonstrates anti-tumor activity in human melanoma xenograft models engrafted with human effector cells and is associated with enhanced macrophage infiltration, enriched monocyte and macrophage gene signatures and pro-inflammatory signaling pathways in the tumor microenvironment. IgE prolongs the survival of patient-derived xenograft-bearing mice reconstituted with autologous immune cells. No ex vivo activation of basophils in patient blood is measured in the presence of CSPG4 IgE. Our findings support a promising IgE-based immunotherapy for melanoma.

Original language	English
Article number	2192
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-37811-3
Publication status	Published - 25 Apr 2023

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

https://doi.org/10.1038/s41467-023-37811-3Licence: CC BY

Chauhan et al Accepted In Press Nature Communications 2023 352160_3_merged_1680280169Accepted author manuscript, 79.7 MBLicence: CC BY
Chauhan et al Nat Commun Published 2023Final published version, 6.73 MBLicence: CC BY

Cite this

@article{95108efda1f04e90bba13c1852bcd376,

title = "Anti-cancer Pro-inflammatory Effects of an IgE Antibody Targeting the Melanoma-associated Antigen Chondroitin Sulfate Proteoglycan 4",

abstract = "Outcomes for half of patients with melanoma remain poor despite standard-of-care checkpoint inhibitor therapies. The prevalence of the melanoma-associated antigen chondroitin sulfate proteoglycan 4 (CSPG4) expression is ~70%, therefore effective immunotherapies directed at CSPG4 could benefit many patients. Since IgE exerts potent immune-activating functions in tissues, we engineer a monoclonal IgE antibody with human constant domains recognizing CSPG4 to target melanoma. CSPG4 IgE binds to human melanomas including metastases, mediates tumoricidal antibody-dependent cellular cytotoxicity and stimulates human IgE Fc-receptor-expressing monocytes towards pro-inflammatory phenotypes. IgE demonstrates anti-tumor activity in human melanoma xenograft models engrafted with human effector cells and is associated with enhanced macrophage infiltration, enriched monocyte and macrophage gene signatures and pro-inflammatory signaling pathways in the tumor microenvironment. IgE prolongs the survival of patient-derived xenograft-bearing mice reconstituted with autologous immune cells. No ex vivo activation of basophils in patient blood is measured in the presence of CSPG4 IgE. Our findings support a promising IgE-based immunotherapy for melanoma.",

author = "Jitesh Chauhan and Melanie Grandits and {Gusmao Ferreira}, {Lais Cristina} and Silvia Mele and Mano Nakamura and {Lopez-Abente Muroz}, Jacobo and Silvia Crescioli and Roman Laddach and {Romero Clavijo}, Pablo and Anthony Cheung and Chara Stavraka and Alicia Chenoweth and Sow, {Heng Sheng} and Giulia Chiaruttini and Amy Gilbert and Tihomir Dodev and Alex Koers and Giulia Pellizzari and Kristina Ilieva and Francis Man and Niwa Ali and Carl Hobbs and Sara Lombardi and Lionarons, {Dani{\"e}l A.} and Gould, {Hannah J.} and Andrew Beavil and Geh, {Jenny L. C.} and {MacKenzie Ross}, {Alastair D} and Ciaran Healy and Eduardo Calonje and Julian Downward and Frank Nestle and Sophia Tsoka and Debra Josephs and Philip Blower and Panagiotis Karagiannis and Lacy, {Katie E.} and James Spicer and Karagiannis, {Sophia N} and Heather Bax",

note = "Funding Information: The authors acknowledge the Biomedical Research Centre (BRC) Immune Monitoring Core Facility team at Guy{\textquoteright}s and St Thomas{\textquoteright} NHS Foundation Trust for flow cytometry facilities and assistance and Ms. Debbie Finch at the Cancer Research UK King{\textquoteright}s Health Partners Centre at King{\textquoteright}s College London for immunohistochemistry support. We thank all healthy volunteers and patients who participated in this study, as well as and colleagues from Guy{\textquoteright}s and St Thomas{\textquoteright} Oncology & Haematology Clinical Trials (OHCT), especially Agnieszka Zielonka, Harriet Gilbert-Jones, Malahat Khaula, and Anna Black for their assistance. The authors are solely responsible for the decision to publish, and the preparation of the manuscript. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The research was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) based at Guy{\textquoteright}s and St Thomas{\textquoteright} NHS Foundation Trust and King{\textquoteright}s College London (IS-BRC-1215-20006; S.N.K.). The authors acknowledge support from Cancer Research UK (C30122/A11527; C30122/A15774; J.S., S.N.K., H.J.B., P.J.B., and H.J.G.); the Medical Research Council (MR/L023091/1; S.N.K., F.O.N., and J.S.); Innovate UK (51746; S.N.K.); the Guy{\textquoteright}s and St Thomas{\textquoteright}s Foundation Trust Charity Melanoma Special Fund (573; S.N.K. and K.E.L.); CRUK/NIHR in England/DoH for Scotland, Wales and Northern Ireland Experimental Cancer Medicine Centre (C10355/A15587; J.S.); The Rotary Foundation of Rotary International (M.N.); the Inman Charity (S.N.K. and G.P.); Breast Cancer Now (147; KCL-BCN-Q3; S.N.K.); the Cancer Research UK King{\textquoteright}s Health Partners Centre at King{\textquoteright}s College London (C604/A25135; J.S.); Cancer Research UK City of London Centre—Studentships award (C7893/A31530; J.D., S.N.K., J.S., and P.R.-C.). Funding Information: The authors acknowledge the Biomedical Research Centre (BRC) Immune Monitoring Core Facility team at Guy{\textquoteright}s and St Thomas{\textquoteright} NHS Foundation Trust for flow cytometry facilities and assistance and Ms. Debbie Finch at the Cancer Research UK King{\textquoteright}s Health Partners Centre at King{\textquoteright}s College London for immunohistochemistry support. We thank all healthy volunteers and patients who participated in this study, as well as and colleagues from Guy{\textquoteright}s and St Thomas{\textquoteright} Oncology & Haematology Clinical Trials (OHCT), especially Agnieszka Zielonka, Harriet Gilbert-Jones, Malahat Khaula, and Anna Black for their assistance. The authors are solely responsible for the decision to publish, and the preparation of the manuscript. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The research was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) based at Guy{\textquoteright}s and St Thomas{\textquoteright} NHS Foundation Trust and King{\textquoteright}s College London (IS-BRC-1215-20006; S.N.K.). The authors acknowledge support from Cancer Research UK (C30122/A11527; C30122/A15774; J.S., S.N.K., H.J.B., P.J.B., and H.J.G.); the Medical Research Council (MR/L023091/1; S.N.K., F.O.N., and J.S.); Innovate UK (51746; S.N.K.); the Guy{\textquoteright}s and St Thomas{\textquoteright}s Foundation Trust Charity Melanoma Special Fund (573; S.N.K. and K.E.L.); CRUK/NIHR in England/DoH for Scotland, Wales and Northern Ireland Experimental Cancer Medicine Centre (C10355/A15587; J.S.); The Rotary Foundation of Rotary International (M.N.); the Inman Charity (S.N.K. and G.P.); Breast Cancer Now (147; KCL-BCN-Q3; S.N.K.); the Cancer Research UK King{\textquoteright}s Health Partners Centre at King{\textquoteright}s College London (C604/A25135; J.S.); Cancer Research UK City of London Centre—Studentships award (C7893/A31530; J.D., S.N.K., J.S., and P.R.-C.). Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = apr,

day = "25",

doi = "https://doi.org/10.1038/s41467-023-37811-3",

language = "English",

volume = "14",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Chauhan, J , Grandits, M , Gusmao Ferreira, LC , Mele, S , Nakamura, M , Lopez-Abente Muroz, J , Crescioli, S , Laddach, R , Romero Clavijo, P , Cheung, A , Stavraka, C , Chenoweth, A , Sow, HS , Chiaruttini, G , Gilbert, A , Dodev, T , Koers, A , Pellizzari, G , Ilieva, K , Man, F , Ali, N, Hobbs, C, Lombardi, S, Lionarons, DA, Gould, HJ, Beavil, A, Geh, JLC, MacKenzie Ross, AD, Healy, C, Calonje, E, Downward, J, Nestle, F , Tsoka, S , Josephs, D , Blower, P , Karagiannis, P, Lacy, KE, Spicer, J , Karagiannis, SN & Bax, H 2023, 'Anti-cancer Pro-inflammatory Effects of an IgE Antibody Targeting the Melanoma-associated Antigen Chondroitin Sulfate Proteoglycan 4', Nature Communications, vol. 14, no. 1, 2192. https://doi.org/10.1038/s41467-023-37811-3

TY - JOUR

T1 - Anti-cancer Pro-inflammatory Effects of an IgE Antibody Targeting the Melanoma-associated Antigen Chondroitin Sulfate Proteoglycan 4

AU - Chauhan, Jitesh

AU - Grandits, Melanie

AU - Gusmao Ferreira, Lais Cristina

AU - Mele, Silvia

AU - Nakamura, Mano

AU - Lopez-Abente Muroz, Jacobo

AU - Crescioli, Silvia

AU - Laddach, Roman

AU - Romero Clavijo, Pablo

AU - Cheung, Anthony

AU - Stavraka, Chara

AU - Chenoweth, Alicia

AU - Sow, Heng Sheng

AU - Chiaruttini, Giulia

AU - Gilbert, Amy

AU - Dodev, Tihomir

AU - Koers, Alex

AU - Pellizzari, Giulia

AU - Ilieva, Kristina

AU - Man, Francis

AU - Ali, Niwa

AU - Hobbs, Carl

AU - Lombardi, Sara

AU - Lionarons, Daniël A.

AU - Gould, Hannah J.

AU - Beavil, Andrew

AU - Geh, Jenny L. C.

AU - MacKenzie Ross, Alastair D

AU - Healy, Ciaran

AU - Calonje, Eduardo

AU - Downward, Julian

AU - Nestle, Frank

AU - Tsoka, Sophia

AU - Josephs, Debra

AU - Blower, Philip

AU - Karagiannis, Panagiotis

AU - Lacy, Katie E.

AU - Spicer, James

AU - Karagiannis, Sophia N

AU - Bax, Heather

N1 - Funding Information: The authors acknowledge the Biomedical Research Centre (BRC) Immune Monitoring Core Facility team at Guy’s and St Thomas’ NHS Foundation Trust for flow cytometry facilities and assistance and Ms. Debbie Finch at the Cancer Research UK King’s Health Partners Centre at King’s College London for immunohistochemistry support. We thank all healthy volunteers and patients who participated in this study, as well as and colleagues from Guy’s and St Thomas’ Oncology & Haematology Clinical Trials (OHCT), especially Agnieszka Zielonka, Harriet Gilbert-Jones, Malahat Khaula, and Anna Black for their assistance. The authors are solely responsible for the decision to publish, and the preparation of the manuscript. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The research was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London (IS-BRC-1215-20006; S.N.K.). The authors acknowledge support from Cancer Research UK (C30122/A11527; C30122/A15774; J.S., S.N.K., H.J.B., P.J.B., and H.J.G.); the Medical Research Council (MR/L023091/1; S.N.K., F.O.N., and J.S.); Innovate UK (51746; S.N.K.); the Guy’s and St Thomas’s Foundation Trust Charity Melanoma Special Fund (573; S.N.K. and K.E.L.); CRUK/NIHR in England/DoH for Scotland, Wales and Northern Ireland Experimental Cancer Medicine Centre (C10355/A15587; J.S.); The Rotary Foundation of Rotary International (M.N.); the Inman Charity (S.N.K. and G.P.); Breast Cancer Now (147; KCL-BCN-Q3; S.N.K.); the Cancer Research UK King’s Health Partners Centre at King’s College London (C604/A25135; J.S.); Cancer Research UK City of London Centre—Studentships award (C7893/A31530; J.D., S.N.K., J.S., and P.R.-C.). Funding Information: The authors acknowledge the Biomedical Research Centre (BRC) Immune Monitoring Core Facility team at Guy’s and St Thomas’ NHS Foundation Trust for flow cytometry facilities and assistance and Ms. Debbie Finch at the Cancer Research UK King’s Health Partners Centre at King’s College London for immunohistochemistry support. We thank all healthy volunteers and patients who participated in this study, as well as and colleagues from Guy’s and St Thomas’ Oncology & Haematology Clinical Trials (OHCT), especially Agnieszka Zielonka, Harriet Gilbert-Jones, Malahat Khaula, and Anna Black for their assistance. The authors are solely responsible for the decision to publish, and the preparation of the manuscript. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The research was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London (IS-BRC-1215-20006; S.N.K.). The authors acknowledge support from Cancer Research UK (C30122/A11527; C30122/A15774; J.S., S.N.K., H.J.B., P.J.B., and H.J.G.); the Medical Research Council (MR/L023091/1; S.N.K., F.O.N., and J.S.); Innovate UK (51746; S.N.K.); the Guy’s and St Thomas’s Foundation Trust Charity Melanoma Special Fund (573; S.N.K. and K.E.L.); CRUK/NIHR in England/DoH for Scotland, Wales and Northern Ireland Experimental Cancer Medicine Centre (C10355/A15587; J.S.); The Rotary Foundation of Rotary International (M.N.); the Inman Charity (S.N.K. and G.P.); Breast Cancer Now (147; KCL-BCN-Q3; S.N.K.); the Cancer Research UK King’s Health Partners Centre at King’s College London (C604/A25135; J.S.); Cancer Research UK City of London Centre—Studentships award (C7893/A31530; J.D., S.N.K., J.S., and P.R.-C.). Publisher Copyright: © 2023, The Author(s).

PY - 2023/4/25

Y1 - 2023/4/25

N2 - Outcomes for half of patients with melanoma remain poor despite standard-of-care checkpoint inhibitor therapies. The prevalence of the melanoma-associated antigen chondroitin sulfate proteoglycan 4 (CSPG4) expression is ~70%, therefore effective immunotherapies directed at CSPG4 could benefit many patients. Since IgE exerts potent immune-activating functions in tissues, we engineer a monoclonal IgE antibody with human constant domains recognizing CSPG4 to target melanoma. CSPG4 IgE binds to human melanomas including metastases, mediates tumoricidal antibody-dependent cellular cytotoxicity and stimulates human IgE Fc-receptor-expressing monocytes towards pro-inflammatory phenotypes. IgE demonstrates anti-tumor activity in human melanoma xenograft models engrafted with human effector cells and is associated with enhanced macrophage infiltration, enriched monocyte and macrophage gene signatures and pro-inflammatory signaling pathways in the tumor microenvironment. IgE prolongs the survival of patient-derived xenograft-bearing mice reconstituted with autologous immune cells. No ex vivo activation of basophils in patient blood is measured in the presence of CSPG4 IgE. Our findings support a promising IgE-based immunotherapy for melanoma.

AB - Outcomes for half of patients with melanoma remain poor despite standard-of-care checkpoint inhibitor therapies. The prevalence of the melanoma-associated antigen chondroitin sulfate proteoglycan 4 (CSPG4) expression is ~70%, therefore effective immunotherapies directed at CSPG4 could benefit many patients. Since IgE exerts potent immune-activating functions in tissues, we engineer a monoclonal IgE antibody with human constant domains recognizing CSPG4 to target melanoma. CSPG4 IgE binds to human melanomas including metastases, mediates tumoricidal antibody-dependent cellular cytotoxicity and stimulates human IgE Fc-receptor-expressing monocytes towards pro-inflammatory phenotypes. IgE demonstrates anti-tumor activity in human melanoma xenograft models engrafted with human effector cells and is associated with enhanced macrophage infiltration, enriched monocyte and macrophage gene signatures and pro-inflammatory signaling pathways in the tumor microenvironment. IgE prolongs the survival of patient-derived xenograft-bearing mice reconstituted with autologous immune cells. No ex vivo activation of basophils in patient blood is measured in the presence of CSPG4 IgE. Our findings support a promising IgE-based immunotherapy for melanoma.

UR - http://www.scopus.com/inward/record.url?scp=85154551617&partnerID=8YFLogxK

U2 - https://doi.org/10.1038/s41467-023-37811-3

DO - https://doi.org/10.1038/s41467-023-37811-3

M3 - Article

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2192

ER -

Anti-cancer Pro-inflammatory Effects of an IgE Antibody Targeting the Melanoma-associated Antigen Chondroitin Sulfate Proteoglycan 4

Abstract

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this