title: Anti-leukemic activity and tolerability of anti-human CD47 monoclonal antibodies.
abstract: CD47, a broadly expressed cell surface protein, inhibits cell phagocytosis via interaction with phagocyte-expressed SIRPα. A variety of hematological malignancies demonstrate elevated CD47 expression, suggesting that CD47 may mediate immune escape. We discovered three unique CD47-SIRPα blocking anti-CD47 monoclonal antibodies (mAbs) with low nano-molar affinity to human and cynomolgus monkey CD47, and no hemagglutination and platelet aggregation activity. To characterize the anti-cancer activity elicited by blocking CD47, the mAbs were cloned into effector function silent and competent Fc backbones. Effector function competent mAbs demonstrated potent activity in vitro and in vivo, while effector function silent mAbs demonstrated minimal activity, indicating that blocking CD47 only leads to a therapeutic effect in the presence of Fc effector function. A non-human primate study revealed that the effector function competent mAb IgG1 C47B222-(CHO) decreased red blood cells (RBC), hematocrit and hemoglobin by >40% at 1 mg/kg, whereas the effector function silent mAb IgG2σ C47B222-(CHO) had minimal impact on RBC indices at 1 and 10 mg/kg. Taken together, our findings suggest that targeting CD47 is an attractive therapeutic anti-cancer approach. However, the anti-cancer activity observed with anti-CD47 mAbs is Fc effector dependent as are the side effects observed on RBC indices.
authors.affiliation: Oncology Discovery, Janssen Research and Development, Spring House, PA, USA.
authors.forename: E C
authors.initials: EC
authors.lastname: Pietsch
authors.affiliation: Biologics Research, Janssen Research and Development, San Diego, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Dong
authors.affiliation: Biologics Research, Janssen Research and Development, Spring House, PA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Cardoso
authors.affiliation: Oncology Discovery, Janssen Research and Development, Spring House, PA, USA.
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Oncology Discovery, Janssen Research and Development, Spring House, PA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Chin
authors.affiliation: Oncology Discovery, Janssen Research and Development, Spring House, PA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Hawkins
authors.affiliation: Biologics Research, Janssen Research and Development, San Diego, CA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Dinh
authors.affiliation: Biologics Research, Janssen Research and Development, San Diego, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Biologics Research, Janssen Research and Development, Spring House, PA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Strake
authors.affiliation: Biologics Research, Janssen Research and Development, San Diego, CA, USA.
authors.forename: P-H
authors.initials: PH
authors.lastname: Feng
authors.affiliation: Biologics Toxicology, Janssen Research and Development, Spring House, PA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Rocca
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: C Dos
authors.initials: CD
authors.lastname: Santos
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: X
authors.initials: X
authors.lastname: Shan
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Danet-Desnoyers
authors.affiliation: Pharmaceutical Development and Manufacturing Sciences, Janssen Research and Development, Malvern, PA, USA.
authors.forename: F
authors.initials: F
authors.lastname: Shi
authors.affiliation: Oncology Discovery, Janssen Research and Development, Spring House, PA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Kaiser
authors.affiliation: Oncology Discovery, Janssen Research and Development, Spring House, PA, USA.
authors.forename: H J
authors.initials: HJ
authors.lastname: Millar
authors.affiliation: Biologics Research, Janssen Research and Development, San Diego, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Fenton
authors.affiliation: Biologics Research, Janssen Research and Development, San Diego, CA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Swanson
authors.affiliation: Oncology Discovery, Janssen Research and Development, Spring House, PA, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Nemeth
authors.affiliation: Oncology Discovery, Janssen Research and Development, Spring House, PA, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Attar
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal; D051928:CD47 Antigen / Q000235:genetics*; D005260:Female; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD
chemical_list: D000911:Antibodies, Monoclonal; D051928:CD47 Antigen; C497894:CD47 protein, human