Novel immunotherapeutics against LGR5 to target multiple cancer types

Hung Chang Chen; Nico Mueller; Katherine Stott; Chrysa Kapeni; Eilidh Rivers; Carolin M. Sauer; Flavio Beke; Stephen J. Walsh; Nicola Ashman; Louise O’Brien; Amir Rafati Fard; Arman Godsinia; Changtai Li; Fadwa Joud; Olivier Giger; Inti Zlobec; Ioana Olan; Sarah J. Aitken; Matthew Hoare; Richard Mair; Eva Serrao; James D. Brenton; Alicia Garcia-Gimenez; Simon E. Richardson; Brian Huntly; David R. Spring; Mikkel Ole Skjoedt; Karsten Skjødt; Marc de la Roche; Maike de la Roche

doi:10.1038/s44321-024-00121-2

Novel immunotherapeutics against LGR5 to target multiple cancer types

Hung Chang Chen, Nico Mueller, Katherine Stott, Chrysa Kapeni, Eilidh Rivers, Carolin M. Sauer, Flavio Beke, Stephen J. Walsh, Nicola Ashman, Louise O’Brien, Amir Rafati Fard, Arman Godsinia, Changtai Li, Fadwa Joud, Olivier Giger, Inti Zlobec, Ioana Olan, Sarah J. Aitken, Matthew Hoare, Richard MairEva Serrao, James D. Brenton, Alicia Garcia-Gimenez, Simon E. Richardson, Brian Huntly, David R. Spring, Mikkel Ole Skjoedt, Karsten Skjødt, Marc de la Roche^*, Maike de la Roche^*

^*Corresponding author for this work

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

2 Citations (Scopus)

Abstract

We have developed and validated a highly specific, versatile antibody to the extracellular domain of human LGR5 (α-LGR5). α-LGR5 detects LGR5 overexpression in >90% of colorectal cancer (CRC), hepatocellular carcinoma (HCC) and pre-B-ALL tumour cells and was used to generate an Antibody-Drug Conjugate (α-LGR5-ADC), Bispecific T-cell Engager (α-LGR5-BiTE) and Chimeric Antigen Receptor (α-LGR5-CAR). α-LGR5-ADC was the most effective modality for targeting LGR5⁺ cancer cells in vitro and demonstrated potent anti-tumour efficacy in a murine model of human NALM6 pre-B-ALL driving tumour attrition to less than 1% of control treatment. α-LGR5-BiTE treatment was less effective in the pre-B-ALL cancer model yet promoted a twofold reduction in tumour burden. α-LGR5-CAR-T cells also showed specific and potent LGR5⁺ cancer cell killing in vitro and effective tumour targeting with a fourfold decrease in pre-B-ALL tumour burden relative to controls. Taken together, we show that α-LGR5 can not only be used as a research tool and a biomarker but also provides a versatile building block for a highly effective immune therapeutic portfolio targeting a range of LGR5-expressing cancer cells.

Original language	English
Pages (from-to)	2233-2261
Number of pages	29
Journal	EMBO Molecular Medicine
Volume	16
Issue number	9
DOIs	https://doi.org/10.1038/s44321-024-00121-2
Publication status	Published - 12 Sept 2024
Externally published	Yes

Keywords

ADC
BiTE
CAR
Cancer Immunotherapeutics
LGR5

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10.1038/s44321-024-00121-2

Cite this

Chen, H. C., Mueller, N., Stott, K., Kapeni, C., Rivers, E., Sauer, C. M., Beke, F., Walsh, S. J., Ashman, N., O’Brien, L., Rafati Fard, A., Godsinia, A., Li, C., Joud, F., Giger, O., Zlobec, I., Olan, I., Aitken, S. J., Hoare, M., ... de la Roche, M. (2024). Novel immunotherapeutics against LGR5 to target multiple cancer types. EMBO Molecular Medicine, 16(9), 2233-2261. https://doi.org/10.1038/s44321-024-00121-2

@article{d6a55f79a7024512a9019f92f4e8b00f,

title = "Novel immunotherapeutics against LGR5 to target multiple cancer types",

abstract = "We have developed and validated a highly specific, versatile antibody to the extracellular domain of human LGR5 (α-LGR5). α-LGR5 detects LGR5 overexpression in >90% of colorectal cancer (CRC), hepatocellular carcinoma (HCC) and pre-B-ALL tumour cells and was used to generate an Antibody-Drug Conjugate (α-LGR5-ADC), Bispecific T-cell Engager (α-LGR5-BiTE) and Chimeric Antigen Receptor (α-LGR5-CAR). α-LGR5-ADC was the most effective modality for targeting LGR5+ cancer cells in vitro and demonstrated potent anti-tumour efficacy in a murine model of human NALM6 pre-B-ALL driving tumour attrition to less than 1% of control treatment. α-LGR5-BiTE treatment was less effective in the pre-B-ALL cancer model yet promoted a twofold reduction in tumour burden. α-LGR5-CAR-T cells also showed specific and potent LGR5+ cancer cell killing in vitro and effective tumour targeting with a fourfold decrease in pre-B-ALL tumour burden relative to controls. Taken together, we show that α-LGR5 can not only be used as a research tool and a biomarker but also provides a versatile building block for a highly effective immune therapeutic portfolio targeting a range of LGR5-expressing cancer cells.",

keywords = "ADC, BiTE, CAR, Cancer Immunotherapeutics, LGR5",

author = "Chen, {Hung Chang} and Nico Mueller and Katherine Stott and Chrysa Kapeni and Eilidh Rivers and Sauer, {Carolin M.} and Flavio Beke and Walsh, {Stephen J.} and Nicola Ashman and Louise O{\textquoteright}Brien and {Rafati Fard}, Amir and Arman Godsinia and Changtai Li and Fadwa Joud and Olivier Giger and Inti Zlobec and Ioana Olan and Aitken, {Sarah J.} and Matthew Hoare and Richard Mair and Eva Serrao and Brenton, {James D.} and Alicia Garcia-Gimenez and Richardson, {Simon E.} and Brian Huntly and Spring, {David R.} and Skjoedt, {Mikkel Ole} and Karsten Skj{\o}dt and {de la Roche}, Marc and {de la Roche}, Maike",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

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day = "12",

doi = "10.1038/s44321-024-00121-2",

language = "English",

volume = "16",

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Chen, HC, Mueller, N, Stott, K, Kapeni, C, Rivers, E, Sauer, CM, Beke, F, Walsh, SJ, Ashman, N, O’Brien, L, Rafati Fard, A, Godsinia, A, Li, C, Joud, F, Giger, O, Zlobec, I, Olan, I, Aitken, SJ, Hoare, M, Mair, R, Serrao, E, Brenton, JD, Garcia-Gimenez, A, Richardson, SE, Huntly, B, Spring, DR, Skjoedt, MO, Skjødt, K, de la Roche, M & de la Roche, M 2024, 'Novel immunotherapeutics against LGR5 to target multiple cancer types', EMBO Molecular Medicine, vol. 16, no. 9, pp. 2233-2261. https://doi.org/10.1038/s44321-024-00121-2

TY - JOUR

T1 - Novel immunotherapeutics against LGR5 to target multiple cancer types

AU - Chen, Hung Chang

AU - Mueller, Nico

AU - Stott, Katherine

AU - Kapeni, Chrysa

AU - Rivers, Eilidh

AU - Sauer, Carolin M.

AU - Beke, Flavio

AU - Walsh, Stephen J.

AU - Ashman, Nicola

AU - O’Brien, Louise

AU - Rafati Fard, Amir

AU - Godsinia, Arman

AU - Li, Changtai

AU - Joud, Fadwa

AU - Giger, Olivier

AU - Zlobec, Inti

AU - Olan, Ioana

AU - Aitken, Sarah J.

AU - Hoare, Matthew

AU - Mair, Richard

AU - Serrao, Eva

AU - Brenton, James D.

AU - Garcia-Gimenez, Alicia

AU - Richardson, Simon E.

AU - Huntly, Brian

AU - Spring, David R.

AU - Skjoedt, Mikkel Ole

AU - Skjødt, Karsten

AU - de la Roche, Marc

AU - de la Roche, Maike

PY - 2024/9/12

Y1 - 2024/9/12

N2 - We have developed and validated a highly specific, versatile antibody to the extracellular domain of human LGR5 (α-LGR5). α-LGR5 detects LGR5 overexpression in >90% of colorectal cancer (CRC), hepatocellular carcinoma (HCC) and pre-B-ALL tumour cells and was used to generate an Antibody-Drug Conjugate (α-LGR5-ADC), Bispecific T-cell Engager (α-LGR5-BiTE) and Chimeric Antigen Receptor (α-LGR5-CAR). α-LGR5-ADC was the most effective modality for targeting LGR5+ cancer cells in vitro and demonstrated potent anti-tumour efficacy in a murine model of human NALM6 pre-B-ALL driving tumour attrition to less than 1% of control treatment. α-LGR5-BiTE treatment was less effective in the pre-B-ALL cancer model yet promoted a twofold reduction in tumour burden. α-LGR5-CAR-T cells also showed specific and potent LGR5+ cancer cell killing in vitro and effective tumour targeting with a fourfold decrease in pre-B-ALL tumour burden relative to controls. Taken together, we show that α-LGR5 can not only be used as a research tool and a biomarker but also provides a versatile building block for a highly effective immune therapeutic portfolio targeting a range of LGR5-expressing cancer cells.

AB - We have developed and validated a highly specific, versatile antibody to the extracellular domain of human LGR5 (α-LGR5). α-LGR5 detects LGR5 overexpression in >90% of colorectal cancer (CRC), hepatocellular carcinoma (HCC) and pre-B-ALL tumour cells and was used to generate an Antibody-Drug Conjugate (α-LGR5-ADC), Bispecific T-cell Engager (α-LGR5-BiTE) and Chimeric Antigen Receptor (α-LGR5-CAR). α-LGR5-ADC was the most effective modality for targeting LGR5+ cancer cells in vitro and demonstrated potent anti-tumour efficacy in a murine model of human NALM6 pre-B-ALL driving tumour attrition to less than 1% of control treatment. α-LGR5-BiTE treatment was less effective in the pre-B-ALL cancer model yet promoted a twofold reduction in tumour burden. α-LGR5-CAR-T cells also showed specific and potent LGR5+ cancer cell killing in vitro and effective tumour targeting with a fourfold decrease in pre-B-ALL tumour burden relative to controls. Taken together, we show that α-LGR5 can not only be used as a research tool and a biomarker but also provides a versatile building block for a highly effective immune therapeutic portfolio targeting a range of LGR5-expressing cancer cells.

KW - ADC

KW - BiTE

KW - CAR

KW - Cancer Immunotherapeutics

KW - LGR5

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U2 - 10.1038/s44321-024-00121-2

DO - 10.1038/s44321-024-00121-2

M3 - Article

C2 - 39169164

AN - SCOPUS:85201604978

SN - 1757-4676

VL - 16

SP - 2233

EP - 2261

JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

IS - 9

ER -

Novel immunotherapeutics against LGR5 to target multiple cancer types

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Keywords

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