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A novel antibody targeting ICOS increases intratumoural cytotoxic to regulatory T cell ratio and induces tumour regression

View ORCID ProfileRichard C.A. Sainson, Anil K. Thotakura, Miha Kosmac, Gwenoline Borhis, Nahida Parveen, Rachael Kimber, Joana Carvalho, Simon Henderson, Kerstin Pryke, Tracey Okell, Siobhan O’Leary, Stuart Ball, Lauriane Gamand, Emma Taggart, Eleanor Pring, Hanif Ali, Hannah Craig, Vivian W. Y. Wong, Qi Liang, Robert J. Rowlands, Morgane Lecointre, Jamie Campbell, Ian Kirby, David Melvin, Volker Germaschewski, Elisabeth Oelmann, Sonia Quaratino, Matthew McCourt
doi: https://doi.org/10.1101/771493
Richard C.A. Sainson
1Kymab Ltd., Babraham Research Campus, Cambridge CB22 3AT, U.K
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  • ORCID record for Richard C.A. Sainson
  • For correspondence: richard.sainson@kymab.com
Anil K. Thotakura
1Kymab Ltd., Babraham Research Campus, Cambridge CB22 3AT, U.K
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Miha Kosmac
1Kymab Ltd., Babraham Research Campus, Cambridge CB22 3AT, U.K
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Gwenoline Borhis
1Kymab Ltd., Babraham Research Campus, Cambridge CB22 3AT, U.K
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Nahida Parveen
1Kymab Ltd., Babraham Research Campus, Cambridge CB22 3AT, U.K
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Rachael Kimber
1Kymab Ltd., Babraham Research Campus, Cambridge CB22 3AT, U.K
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Joana Carvalho
1Kymab Ltd., Babraham Research Campus, Cambridge CB22 3AT, U.K
4SNIPR BIOME, Lersø Parkallé 44, 2100 Copenhagen Denmark
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Simon Henderson
1Kymab Ltd., Babraham Research Campus, Cambridge CB22 3AT, U.K
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Kerstin Pryke
1Kymab Ltd., Babraham Research Campus, Cambridge CB22 3AT, U.K
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Tracey Okell
1Kymab Ltd., Babraham Research Campus, Cambridge CB22 3AT, U.K
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Siobhan O’Leary
1Kymab Ltd., Babraham Research Campus, Cambridge CB22 3AT, U.K
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Stuart Ball
1Kymab Ltd., Babraham Research Campus, Cambridge CB22 3AT, U.K
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Lauriane Gamand
1Kymab Ltd., Babraham Research Campus, Cambridge CB22 3AT, U.K
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Emma Taggart
1Kymab Ltd., Babraham Research Campus, Cambridge CB22 3AT, U.K
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Eleanor Pring
1Kymab Ltd., Babraham Research Campus, Cambridge CB22 3AT, U.K
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Hanif Ali
1Kymab Ltd., Babraham Research Campus, Cambridge CB22 3AT, U.K
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Hannah Craig
1Kymab Ltd., Babraham Research Campus, Cambridge CB22 3AT, U.K
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Vivian W. Y. Wong
1Kymab Ltd., Babraham Research Campus, Cambridge CB22 3AT, U.K
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Qi Liang
1Kymab Ltd., Babraham Research Campus, Cambridge CB22 3AT, U.K
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Robert J. Rowlands
1Kymab Ltd., Babraham Research Campus, Cambridge CB22 3AT, U.K
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Morgane Lecointre
1Kymab Ltd., Babraham Research Campus, Cambridge CB22 3AT, U.K
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Jamie Campbell
1Kymab Ltd., Babraham Research Campus, Cambridge CB22 3AT, U.K
2Abcam plc, Discovery Drive, Cambridge Biomedical Campus, Cambridge CB2 0AX
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Ian Kirby
1Kymab Ltd., Babraham Research Campus, Cambridge CB22 3AT, U.K
3ADC Therapeutics, 42 New Road London, E1 2AX, UK
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David Melvin
1Kymab Ltd., Babraham Research Campus, Cambridge CB22 3AT, U.K
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Volker Germaschewski
1Kymab Ltd., Babraham Research Campus, Cambridge CB22 3AT, U.K
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Elisabeth Oelmann
1Kymab Ltd., Babraham Research Campus, Cambridge CB22 3AT, U.K
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Sonia Quaratino
1Kymab Ltd., Babraham Research Campus, Cambridge CB22 3AT, U.K
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Matthew McCourt
1Kymab Ltd., Babraham Research Campus, Cambridge CB22 3AT, U.K
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Abstract

The immunosuppressive tumour microenvironment constitutes a significant hurdle to the response to immune checkpoint inhibitors. Both soluble factors and specialised immune cells such as regulatory T cells (TReg) are key components of active intratumoural immunosuppression. Previous studies have shown that Inducible Co-Stimulatory receptor (ICOS) is highly expressed in the tumour microenvironment, especially on TReg, suggesting that it represents a relevant target for preferential depletion of these cells. Here, we used immune profiling of samples from tumour bearing mice and cancer patients to characterise the expression of ICOS in different tissues and solid tumours. By immunizing an Icos knockout transgenic mouse line expressing antibodies with human variable domains, we selected a fully human IgG1 antibody called KY1044 that binds ICOS from different species. Using KY1044, we demonstrated that we can exploit the differential expression of ICOS on T cell subtypes to modify the tumour microenvironment and thereby improve the anti-tumour immune response. We showed that KY1044 induces sustained depletion of ICOShigh TReg cells in mouse tumours and depletion of ICOShigh T cells in the blood of non-human primates, but was also associated with secretion of pro-inflammatory cytokines from ICOSlow TEFF cells. Altogether, KY1044 improved the intratumoural TEFF:TReg ratio and increased activation of TEFF cells, resulting in monotherapy efficacy or in synergistic combinatorial efficacy when administered with the immune checkpoint blocker anti-PD-L1. In summary, our data demonstrate that targeting ICOS with KY1044 can favourably alter the intratumoural immune contexture, promoting an anti-tumour response.

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Posted September 16, 2019.
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A novel antibody targeting ICOS increases intratumoural cytotoxic to regulatory T cell ratio and induces tumour regression
Richard C.A. Sainson, Anil K. Thotakura, Miha Kosmac, Gwenoline Borhis, Nahida Parveen, Rachael Kimber, Joana Carvalho, Simon Henderson, Kerstin Pryke, Tracey Okell, Siobhan O’Leary, Stuart Ball, Lauriane Gamand, Emma Taggart, Eleanor Pring, Hanif Ali, Hannah Craig, Vivian W. Y. Wong, Qi Liang, Robert J. Rowlands, Morgane Lecointre, Jamie Campbell, Ian Kirby, David Melvin, Volker Germaschewski, Elisabeth Oelmann, Sonia Quaratino, Matthew McCourt
bioRxiv 771493; doi: https://doi.org/10.1101/771493
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A novel antibody targeting ICOS increases intratumoural cytotoxic to regulatory T cell ratio and induces tumour regression
Richard C.A. Sainson, Anil K. Thotakura, Miha Kosmac, Gwenoline Borhis, Nahida Parveen, Rachael Kimber, Joana Carvalho, Simon Henderson, Kerstin Pryke, Tracey Okell, Siobhan O’Leary, Stuart Ball, Lauriane Gamand, Emma Taggart, Eleanor Pring, Hanif Ali, Hannah Craig, Vivian W. Y. Wong, Qi Liang, Robert J. Rowlands, Morgane Lecointre, Jamie Campbell, Ian Kirby, David Melvin, Volker Germaschewski, Elisabeth Oelmann, Sonia Quaratino, Matthew McCourt
bioRxiv 771493; doi: https://doi.org/10.1101/771493

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