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Title

Preclinical development of a bispecific antibody that safely and effectively targets CD19 and CD47 for the treatment of B cell lymphoma and leukemia
Authors
Buatois, Vanessa
Johnson, Zoë
CollaborationWith : D'Asaro, Matilde / Matthes, Thomas
Published in Molecular Cancer Therapeutics. 2018
Abstract CD47, a ubiquitously expressed innate immune checkpoint receptor that serves as a universal "don't eat me" signal of phagocytosis, is often up-regulated by hematological 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 co-engage CD47 and CD19 selectively on B cells. NI-1701 demonstrates favorable elimination kinetics with no deleterious effects seen on hematological parameters following single or multiple administrations to non-human 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 co-engagement 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 co-administered 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.
Identifiers
PMID: 29743205
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Article (Accepted version) (2.3 MB) - public document Free access
Structures
Faculté de médecine / Section de médecine clinique / Département de médecine
Research group Analyses cellulaires et moléculaires des hémopathies malignes (929)
Citation
(ISO format) 		BUATOIS, Vanessa, JOHNSON, Zoë. Preclinical development of a bispecific antibody that safely and effectively targets CD19 and CD47 for the treatment of B cell lymphoma and leukemia. In: Molecular Cancer Therapeutics, 2018. doi: 10.1158/1535-7163.MCT-17-1095 https://archive-ouverte.unige.ch/unige:104881

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Deposited on : 2018-06-01

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