Journal Article
. 2020 Sep; 8(2):.
doi: 10.1136/jitc-2020-000860.

CD25-targeted antibody-drug conjugate depletes regulatory T cells and eliminates established syngeneic tumors via antitumor immunity

Francesca Zammarchi 1 Karin Havenith 2 Francois Bertelli 3 Balakumar Vijayakrishnan 3 Simon Chivers 2 Patrick H van Berkel 2 
Affiliations
  • PMID: 32912922
  •     26 References
  •     6 citations

Abstract

Background: Regulatory T cells (Tregs) contribute to an immunosuppressive tumor microenvironment. They play an important role in the establishment and progression of tumors with high Tregs infiltration and present a major obstacle to tumor eradication by immunotherapies. Numerous strategies have been attempted to deplete or block Tregs, although their success has been limited.

Methods: A CD25-targeted, pyrrolobenzodiazepine (PBD) dimer-based antibody-drug conjugate (ADC) was investigated for its ability to deplete Tregs and induce antitumor immunity. Antitumor activity of CD25-ADC either alone or in combination with an anti-programmed cell death protein 1 (PD-1) antibody was evaluated in CD25-negative syngeneic models that exhibit tumor infiltration of CD25-expressing Tregs, and its pharmacodynamics and pharmacokinetics were assessed.

Results: Single low doses of CD25-ADC resulted in potent and durable antitumor activity in established syngeneic solid tumor models and the combination of a suboptimal dose was synergistic with PD-1 blockade. Tumor eradication by the CD25-targeted ADC was CD8+ T cell-dependent and CD25-ADC induced protective immunity. Importantly, while CD25-ADC mediated a significant and sustained intratumoral Tregs depletion, accompanied by a concomitant increase in the number of activated and proliferating tumor-infiltrating CD8+ T effector cells, systemic Tregs depletion was transient, alleviating concerns of potential autoimmune side effects.

Conclusions: This study shows that a PBD dimer-based, CD25-targeted ADC is able to deplete Tregs and eradicate established tumors via antitumor immunity. This represents a novel approach to efficiently deplete Tregs via a very potent DNA damaging toxin known to induce immunogenic cell death. Moreover, this study provides proof of concept for a completely new application of ADCs as immunotherapeutic agents, as the main mode of action relies on the ADC directly targeting immune cells, rather than tumor cells. These strong preclinical data warrant the clinical evaluation of camidanlumab tesirine (ADCT-301), a PBD-based ADC targeting human CD25, either alone or in combination with checkpoint inhibitors in solid tumors with known Tregs infiltration. A phase I trial (NCT03621982) of camidanlumab tesirine in patients with selected advanced solid tumors is ongoing.

Keywords: immunotherapy.

Intratumoral depletion of regulatory T cells using CD25-targeted photodynamic therapy in a mouse melanoma model induces antitumoral immune responses.
Dong Sun Oh, Heegon Kim, +4 authors, Heung Kyu Lee.
Oncotarget, 2017 May 26; 8(29). PMID: 28537894    Free PMC article.
Spatially selective depletion of tumor-associated regulatory T cells with near-infrared photoimmunotherapy.
Kazuhide Sato, Noriko Sato, +5 authors, Hisataka Kobayashi.
Sci Transl Med, 2016 Aug 19; 8(352). PMID: 27535621    Free PMC article.
Tumor-Associated Macrophages Can Contribute to Antitumor Activity through FcγR-Mediated Processing of Antibody-Drug Conjugates.
Fu Li, Michelle Ulrich, +6 authors, Che-Leung Law.
Mol Cancer Ther, 2017 Mar 28; 16(7). PMID: 28341790
The emerging role of anti-CD25 directed therapies as both immune modulators and targeted agents in cancer.
Michael J Flynn, John A Hartley.
Br J Haematol, 2017 May 31; 179(1). PMID: 28556984
Review.
Defining the optimal murine models to investigate immune checkpoint blockers and their combination with other immunotherapies.
M F Sanmamed, C Chester, I Melero, H Kohrt.
Ann Oncol, 2016 Feb 26; 27(7). PMID: 26912558
Review.
Targeting regulatory T cells.
Christine Ménétrier-Caux, Tyler Curiel, +3 authors, Weiping Zou.
Target Oncol, 2012 Feb 14; 7(1). PMID: 22327882
Review.
Immune checkpoint inhibitors in cancer therapy: a focus on T-regulatory cells.
Varun Sasidharan Nair, Eyad Elkord.
Immunol Cell Biol, 2018 Jan 24; 96(1). PMID: 29359507
Highly Cited. Review.
APOMAB Antibody-Drug Conjugates Targeting Dead Tumor Cells are Effective In Vivo.
Alexander H Staudacher, Yanrui Li, +6 authors, Michael P Brown.
Mol Cancer Ther, 2018 Nov 11; 18(2). PMID: 30413648
Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma.
Tyler R Simpson, Fubin Li, +11 authors, Sergio A Quezada.
J Exp Med, 2013 Jul 31; 210(9). PMID: 23897981    Free PMC article.
Highly Cited.
ADCT-402, a PBD dimer-containing antibody drug conjugate targeting CD19-expressing malignancies.
Francesca Zammarchi, Simon Corbett, +13 authors, Patrick H van Berkel.
Blood, 2018 Jan 05; 131(10). PMID: 29298756
T-cell tolerance and the multi-functional role of IL-2R signaling in T-regulatory cells.
Guoyan Cheng, Aixin Yu, Thomas R Malek.
Immunol Rev, 2011 Apr 15; 241(1). PMID: 21488890    Free PMC article.
Highly Cited. Review.
T-regulatory cells: key players in tumor immune escape and angiogenesis.
Andrea Facciabene, Gregory T Motz, George Coukos.
Cancer Res, 2012 May 03; 72(9). PMID: 22549946    Free PMC article.
Highly Cited. Review.
Fate of Antibody-Drug Conjugates in Cancer Cells.
Cécile Chalouni, Sophia Doll.
J Exp Clin Cancer Res, 2018 Feb 08; 37(1). PMID: 29409507    Free PMC article.
Review.
Pre-clinical pharmacology and mechanism of action of SG3199, the pyrrolobenzodiazepine (PBD) dimer warhead component of antibody-drug conjugate (ADC) payload tesirine.
John A Hartley, Michael J Flynn, +15 authors, Philip W Howard.
Sci Rep, 2018 Jul 12; 8(1). PMID: 29992976    Free PMC article.
Emerging Functions of Regulatory T Cells in Tissue Homeostasis.
Amit Sharma, Dipayan Rudra.
Front Immunol, 2018 Jun 12; 9. PMID: 29887862    Free PMC article.
Highly Cited. Review.
Depletion of regulatory T cells in tumors with an anti-CD25 immunotoxin induces CD8 T cell-mediated systemic antitumor immunity.
Masanori Onda, Kazuto Kobayashi, Ira Pastan.
Proc Natl Acad Sci U S A, 2019 Feb 15; 116(10). PMID: 30760587    Free PMC article.
Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors.
Frederick Arce Vargas, Andrew J S Furness, +29 authors, Sergio A Quezada.
Immunity, 2017 Apr 16; 46(4). PMID: 28410988    Free PMC article.
Highly Cited.
Antibody-drug conjugates as novel anti-cancer chemotherapeutics.
Christina Peters, Stuart Brown.
Biosci Rep, 2015 Jul 17; 35(4). PMID: 26182432    Free PMC article.
Highly Cited. Review.
High and low affinity IL 2 receptors: analysis by IL 2 dissociation rate and reactivity with monoclonal anti-receptor antibody PC61.
J W Lowenthal, P Corthésy, +3 authors, M Nabholz.
J Immunol, 1985 Dec 01; 135(6). PMID: 3934270
Highly Cited.
ADCT-301, a Pyrrolobenzodiazepine (PBD) Dimer-Containing Antibody-Drug Conjugate (ADC) Targeting CD25-Expressing Hematological Malignancies.
Michael J Flynn, Francesca Zammarchi, +15 authors, John A Hartley.
Mol Cancer Ther, 2016 Nov 04; 15(11). PMID: 27535974
Second-generation IL-2 receptor-targeted diphtheria fusion toxin exhibits antitumor activity and synergy with anti-PD-1 in melanoma.
Laurene S Cheung, Juan Fu, +10 authors, William R Bishai.
Proc Natl Acad Sci U S A, 2019 Feb 06; 116(8). PMID: 30718426    Free PMC article.
Assessing interactions for fixed-dose drug combinations in tumor xenograft studies.
Jianrong Wu, Lorraine Tracey, Andrew M Davidoff.
J Biopharm Stat, 2012 Mar 16; 22(3). PMID: 22416839    Free PMC article.
The role of interleukin-2 during homeostasis and activation of the immune system.
Onur Boyman, Jonathan Sprent.
Nat Rev Immunol, 2012 Feb 22; 12(3). PMID: 22343569
Highly Cited. Review.
Antibody-Drug Conjugates Bearing Pyrrolobenzodiazepine or Tubulysin Payloads Are Immunomodulatory and Synergize with Multiple Immunotherapies.
Jonathan Rios-Doria, Jay Harper, +17 authors, Robert Hollingsworth.
Cancer Res, 2017 Mar 12; 77(10). PMID: 28283653
Antibody drug conjugates and bystander killing: is antigen-dependent internalisation required?
Alexander H Staudacher, Michael P Brown.
Br J Cancer, 2017 Oct 25; 117(12). PMID: 29065110    Free PMC article.
Review.
Cancer immunotherapy beyond immune checkpoint inhibitors.
Julian A Marin-Acevedo, Aixa E Soyano, +2 authors, Yanyan Lou.
J Hematol Oncol, 2018 Jan 14; 11(1). PMID: 29329556    Free PMC article.
Highly Cited. Review.
Regulatory T-Cells as an Emerging Barrier to Immune Checkpoint Inhibition in Lung Cancer.
Daniel R Principe, Lauren Chiec, Nisha A Mohindra, Hidayatullah G Munshi.
Front Oncol, 2021 Jun 19; 11. PMID: 34141625    Free PMC article.
Review.
Antibody-Drug Conjugates for the Treatment of Acute Pediatric Leukemia.
Jamie L Stokke, Deepa Bhojwani.
J Clin Med, 2021 Aug 28; 10(16). PMID: 34441852    Free PMC article.
Review.
Super-enhancer-based identification of a BATF3/IL-2R-module reveals vulnerabilities in anaplastic large cell lymphoma.
Huan-Chang Liang, Mariantonia Costanza, +40 authors, Olaf Merkel.
Nat Commun, 2021 Sep 24; 12(1). PMID: 34552066    Free PMC article.
Therapeutic Implications of Tumor Microenvironment in Lung Cancer: Focus on Immune Checkpoint Blockade.
Carlo Genova, Chiara Dellepiane, +7 authors, Michela Croce.
Front Immunol, 2022 Jan 25; 12. PMID: 35069581    Free PMC article.
Review.
Acute Interstitial Nephritis Triggered by a Novel Anti-CD25 Antibody-Drug Conjugate, Camidanlumab Tesirine.
Nicholas L Li, Karen Flores, +2 authors, Isabelle Ayoub.
Kidney Int Rep, 2022 Mar 09; 7(3). PMID: 35257078    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.