CD25-Treg-depleting antibodies preserving IL-2 signaling on effector T cells enhance effector activation and antitumor immunity

Isabelle Solomon ¹, Maria Amann ², Anne Goubier ³, Frederick Arce Vargas ¹, Dimitrios Zervas ¹, Chen Qing ¹, Jake Y Henry ¹, Ehsan Ghorani ¹, Ayse U Akarca ⁴, Teresa Marafioti ⁴, Anna Śledzińska ¹, Mariana Werner Sunderland ¹, Dafne Franz Demane ¹, Joanne Ruth Clancy ¹, Andrew Georgiou ¹, Josephine Salimu ³, Pascal Merchiers ³, Mark Adrian Brown ³, Reto Flury ⁵, Jan Eckmann ⁶, Claudio Murgia ⁵, Johannes Sam ⁵, Bjoern Jacobsen ⁷, Estelle Marrer-Berger ⁷, Christophe Boetsch ⁷, Sara Belli ⁷, Lea Leibrock ⁷, Joerg Benz ⁷, Hans Koll ⁶, Roger Sutmuller ⁵, Karl S Peggs ⁸, Sergio A Quezada ⁹

Affiliations

¹ Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK.
² Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Schlieren, Switzerland. Maria.Amann@Roche.com.
³ Tusk Therapeutics Ltd., Stevenage Bioscience Catalyst, Stevenage, UK.
⁴ Department of Cellular Pathology, University College London Hospital, London, UK.
⁵ Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Schlieren, Switzerland.
⁶ Roche Innovation Center Munich, Roche Pharmaceutical Research and Development (pRED), Penzberg, Germany.
⁷ Roche Innovation Center Basel, Roche Pharmaceutical Research and Development (pRED), Basel, Switzerland.
⁸ Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK. k.peggs@ucl.ac.uk.
⁹ Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK. s.quezada@ucl.ac.uk.

PMID: 33644766
51 References
19 citations

Abstract

Intratumoral regulatory T cell (Treg) abundance associates with diminished anti-tumor immunity and poor prognosis in human cancers. Recent work demonstrates that CD25, the high affinity receptor subunit for IL-2, is a selective target for Treg depletion in mouse and human malignancies; however, anti-human CD25 antibodies have failed to deliver clinical responses against solid tumors due to bystander IL-2 receptor signaling blockade on effector T cells, which limits their anti-tumor activity. Here we demonstrate potent single-agent activity of anti-CD25 antibodies optimized to deplete Tregs whilst preserving IL-2-STAT5 signaling on effector T cells, and demonstrate synergy with immune checkpoint blockade in vivo. Pre-clinical evaluation of an anti-human CD25 (RG6292) antibody with equivalent features demonstrates, in both non-human primates and humanized mouse models, efficient Treg depletion with no overt immune-related toxicities. Our data supports the clinical development of RG6292 and evaluation of novel combination therapies incorporating non-IL-2 blocking anti-CD25 antibodies in clinical studies.

Other Links

Free PMC article
Full text on Nature cancer

References
Cited By

References
Depletion of CD25+ regulatory cells results in suppression of melanoma growth and induction of autoreactivity in mice. Emma Jones, Michaela Dahm-Vicker, +4 authors, Awen Gallimore. less Cancer Immun, 2003 May 16; 2. PMID: 12747746
Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. S Onizuka, I Tawara, +3 authors, J Shimizu, S Sakaguchi, T Fujita, E Nakayama. less Cancer Res, 1999 Jul 09; 59(13). PMID: 10397255 Highly Cited.
Basiliximab, mechanism of action and pharmacological properties. Elvedina Kapic, Fahir Becic, Jasna Kusturica. Med Arh, 2005 Jan 15; 58(6). PMID: 15648237 Review.

Citedby
The Impact of Tregs on the Anticancer Immunity and the Efficacy of Immune Checkpoint Inhibitor Therapies. Jose M González-Navajas, Dengxia Denise Fan, +4 authors, Jongdae Lee. less Front Immunol, 2021 Mar 16; 12. PMID: 33717139 Free PMC article. Review.
Hyperprogressive Disease: Main Features and Key Controversies. Hugo Arasanz, Miren Zuazo, +15 authors, Ruth Vera. less Int J Mol Sci, 2021 May 01; 22(7). PMID: 33916696 Free PMC article. Review.
Glycosylation of Immune Receptors in Cancer. Ruoxuan Sun, Alyssa Min Jung Kim, Seung-Oe Lim. Cells, 2021 Jun 03; 10(5). PMID: 34064396 Free PMC article. Review.
Perspectives in Melanoma: meeting report from the Melanoma Bridge (December 3rd-5th, 2020, Italy). Paolo A Ascierto, Christian Blank, +20 authors, Magdalena Thurin. less J Transl Med, 2021 Jul 02; 19(1). PMID: 34193182 Free PMC article.
Statins act as transient type I interferon inhibitors to enable the antitumor activity of modified vaccinia Ankara viral vectors. Shirley Tenesaca, Marcos Vasquez, +10 authors, Pedro Berraondo. less J Immunother Cancer, 2021 Jul 30; 9(7). PMID: 34321273 Free PMC article.
Mechanisms of regulatory T cell infiltration in tumors: implications for innovative immune precision therapies. Hiroyoshi Nishikawa, Shohei Koyama. J Immunother Cancer, 2021 Aug 01; 9(7). PMID: 34330764 Free PMC article. Review.
Regulatory T Cells in Autoimmunity and Cancer: A Duplicitous Lifestyle. Aikaterini Hatzioannou, Athina Boumpas, +4 authors, Panayotis Verginis. less Front Immunol, 2021 Sep 21; 12. PMID: 34539668 Free PMC article. Review.
Transient regulatory T-cell targeting triggers immune control of multiple myeloma and prevents disease progression. Julia Dahlhoff, Hannah Manz, +13 authors, Andreas Beilhack. less Leukemia, 2021 Sep 30; 36(3). PMID: 34584204 Free PMC article.
Antibody-guided design and identification of CD25-binding small antibody mimetics using mammalian cell surface display. Kyra See, Tetsuya Kadonosono, +9 authors, Shinae Kizaka-Kondoh. less Sci Rep, 2021 Nov 13; 11(1). PMID: 34764369 Free PMC article.
Targeted Anti-Tumor Immunotherapy Using Tumor Infiltrating Cells. Yifan Xie, Feng Xie, +7 authors, Fangfang Zhou. less Adv Sci (Weinh), 2021 Oct 19; 8(22). PMID: 34658167 Free PMC article. Review.
Pushing Past the Blockade: Advancements in T Cell-Based Cancer Immunotherapies. Jessica Waibl Polania, Emily C Lerner, +2 authors, Peter E Fecci. less Front Immunol, 2021 Dec 07; 12. PMID: 34868044 Free PMC article. Review.
The Blockade of Interleukin-2 During the Acute Phase of Trypanosoma cruzi Infection Reveals Its Dominant Regulatory Role. Jorge Nihei, Fabiola Cardillo, Jose Mengel. Front Cell Infect Microbiol, 2021 Dec 07; 11. PMID: 34869064 Free PMC article.
Potential Reasons for Unresponsiveness to Anti-PD1 Immunotherapy in Young Patients with Advanced Melanoma. Devayani Machiraju, Sarah Schäfer, Jessica C Hassel. Life (Basel), 2021 Dec 25; 11(12). PMID: 34947849 Free PMC article. Review.
Vectorized Treg-depleting αCTLA-4 elicits antigen cross-presentation and CD8+ T cell immunity to reject 'cold' tumors. Monika Semmrich, Jean-Baptiste Marchand, +15 authors, Björn Frendéus. less J Immunother Cancer, 2022 Jan 22; 10(1). PMID: 35058324 Free PMC article.
Anti-CCR4 treatment depletes regulatory T cells and leads to clinical activity in a canine model of advanced prostate cancer. Shingo Maeda, Tomoki Motegi, +8 authors, Yasuyuki Momoi. less J Immunother Cancer, 2022 Feb 09; 10(2). PMID: 35131860 Free PMC article.
Key Players of the Immunosuppressive Tumor Microenvironment and Emerging Therapeutic Strategies. Kevin Park, Mysore S Veena, Daniel Sanghoon Shin. Front Cell Dev Biol, 2022 Mar 30; 10. PMID: 35345849 Free PMC article. Review.
Direct targeting of FOXP3 in Tregs with AZD8701, a novel antisense oligonucleotide to relieve immunosuppression in cancer. Alexey Revenko, Larissa S Carnevalli, +25 authors, A Robert MacLeod. less J Immunother Cancer, 2022 Apr 08; 10(4). PMID: 35387780 Free PMC article.
Immunosuppressive cells in cancer: mechanisms and potential therapeutic targets. Yan Tie, Fan Tang, Yu-Quan Wei, Xia-Wei Wei. J Hematol Oncol, 2022 May 19; 15(1). PMID: 35585567 Free PMC article. Review.
Novel Immunotherapies for Osteosarcoma. Yubao Lu, Jiahe Zhang, +4 authors, Cangyu Zhang. less Front Oncol, 2022 Apr 19; 12. PMID: 35433427 Free PMC article. Review.

BioKDE: Biomedical Knowledge Discovery Engine

Abstract

Other Links