In vitro and in vivo efficacy of an anti-CD203c conjugated antibody (AGS-16C3F) in mouse models of advanced systemic mastocytosis

  • Blood Adv. 2019 Feb 26;3(4):633-643. doi: 10.1182/bloodadvances.2018026179.
Yanyan Zhang  1  2  3 ,  Ghaith Wedeh  4  5 ,  Liang He  1  2  3 ,  Monika Wittner  1  2  3 ,  Florian Beghi  1  2  3 ,  Viviane Baral  1  2  3 ,  Jean-Marie Launay  6 ,  Siham Bibi  4 ,  Fernando Doñate  7 ,  Hosein Kouros-Mehr  8 ,  Michel Arock  4  9 ,  Fawzia Louache  1  2  3  9
Affiliations
  • 1. INSERM, Unité Mixte de Recherche (UMR) 1170, Villejuif, France.
  • 2. Université Paris-Saclay, Gustave Roussy, Villejuif, France.
  • 3. Gustave Roussy, Villejuif, France.
  • 4. Laboratoire de Biologie et Pharmacologie Appliquée, Centre National de la Recherche Scientifique (CNRS) UMR8113, Ecole Normale Supérieure de Cachan, Cachan, France.
  • 5. Faculty of Pharmacy, Tishreen University, Latakia, Syria.
  • 6. Agensys, Inc., Santa Monica, CA.
  • 7. Fulcrum 2020, Los Angeles, CA.
  • 8. Laboratory of Hematology, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; and.
  • 9. CNRS Groupement de Recherche 3697 MicroNiT, Villejuif, France.
PMID: 30804017 DOI: 10.1182/bloodadvances.2018026179
Abstract

Antibody-drug conjugates (ADCs) are a new class of therapeutics that use antibodies to deliver potent cytotoxic drugs selectively to Cancer cells. CD203c, an ecto-nucleotide pyrophosphatase-phosphodiesterase 3, is overexpressed on neoplastic mast cells (MCs) in systemic mastocytosis (SM), thus representing a promising target for antibody-mediated therapy. In this study, we have found that human neoplastic MC lines (ROSAKIT D816V and ROSAKIT D816V-Gluc), which express high levels of CD203c, are highly and specifically sensitive to the antiproliferative effects of an ADC against CD203c (AGS-16C3F). In these cell lines, AGS-16C3F induced cell Apoptosis at very low concentrations. To characterize the effects of AGS-16C3F on leukemia progression in vivo, ROSAKIT D816V-Gluc NOD-SCID γ mouse models of advanced SM (AdvSM) were treated with AGS-16C3F or an ADC control for 2 weeks. Whereas AGS-16C3F had no apparent toxicity in xenotransplanted mice, in vivo neoplastic MC burden significantly decreased in both hematopoietic and nonhematopoietic organs. Furthermore, Animals treated with AGS-16C3F had prolonged survival compared with the Animals treated with control ADC, and AGS-16C3F efficiently prevented disease relapse. In conclusion, these preclinical studies identified CD203c as a novel therapeutic target on neoplastic MCs, and AGS-16C3F as a promising ADC for the treatment of patients with AdvSM.

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