Preclinical Development of a Bispecific Antibody that Safely and Effectively Targets CD19 and CD47 for the Treatment of B-Cell Lymphoma and Leukemia - Université de Rennes Accéder directement au contenu
Article Dans Une Revue Molecular Cancer Therapeutics Année : 2018

Preclinical Development of a Bispecific Antibody that Safely and Effectively Targets CD19 and CD47 for the Treatment of B-Cell Lymphoma and Leukemia

Vanessa Buatois
  • Fonction : Auteur
Zoë Johnson
  • Fonction : Auteur
Anne Papaioannou
  • Fonction : Auteur
Eric Hatterer
  • Fonction : Auteur
Xavier Chauchet
  • Fonction : Auteur
Françoise Richard
  • Fonction : Auteur
Leticia Barba
  • Fonction : Auteur
Bruno Daubeuf
  • Fonction : Auteur
Laura Cons
  • Fonction : Auteur
Lucile Broyer
  • Fonction : Auteur
Matilde d'Asaro
  • Fonction : Auteur
Thomas Matthes
  • Fonction : Auteur
Robert K. Clarke Hinojosa
  • Fonction : Auteur
Eulàlia Genescà Ferrer
  • Fonction : Auteur
José María Ribera
  • Fonction : Auteur
Krzysztof Masternak
  • Fonction : Auteur
Nicolas Fischer
  • Fonction : Auteur
Limin Shang
  • Fonction : Auteur
Walter G. Ferlin
  • Fonction : Auteur correspondant

Résumé

CD47, an ubiquitously expressed innate immune checkpoint receptor that serves as a universal "don't eat me" signal of phagocytosis, is often upregulated by hematologic and solid cancers to evade immune surveillance. Development of CD47-targeted modalities is hindered by the ubiquitous expression of the target, often leading to rapid drug elimination and hemotoxicity including anemia. To overcome such liabilities, we have developed a fully human bispecific antibody, NI-1701, designed to coengage CD47 and CD19 selectively on B cells. NI-1701 demonstrates favorable elimination kinetics with no deleterious effects seen on hematologic parameters following single or multiple administrations to nonhuman primates. Potent in vitro and in vivo activity is induced by NI-1701 to kill cancer cells across a plethora of B-cell malignancies and control tumor growth in xenograft mouse models. The mechanism affording maximal tumor growth inhibition by NI-1701 is dependent on the coengagement of CD47/CD19 on B cells inducing potent antibody-dependent cellular phagocytosis of the targeted cells. NI-1701-induced control of tumor growth in immunodeficient NOD/SCID mice was more effective than that achieved with the anti-CD20 targeted antibody, rituximab. Interestingly, a synergistic effect was seen when tumor-implanted mice were coadministered NI-1701 and rituximab leading to significantly improved tumor growth inhibition and regression in some animals. We describe herein, a novel bispecific antibody approach aimed at sensitizing B cells to become more readily phagocytosed and eliminated thus offering an alternative or adjunct therapeutic option to patients with B-cell malignancies refractory/resistant to anti-CD20-targeted therapy.
Fichier principal
Vignette du fichier
Buatois-2018-Preclinical Development of a Bispecific Antibody.pdf (2.58 Mo) Télécharger le fichier
Origine : Fichiers produits par l'(les) auteur(s)
Loading...

Dates et versions

hal-02474041 , version 1 (23-03-2020)

Identifiants

Citer

Vanessa Buatois, Zoë Johnson, Susana Salgado-Pires, Anne Papaioannou, Eric Hatterer, et al.. Preclinical Development of a Bispecific Antibody that Safely and Effectively Targets CD19 and CD47 for the Treatment of B-Cell Lymphoma and Leukemia. Molecular Cancer Therapeutics, 2018, 17 (8), pp.1739-1751. ⟨10.1158/1535-7163.MCT-17-1095⟩. ⟨hal-02474041⟩
75 Consultations
97 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More