title: FcγRs Modulate the Anti-tumor Activity of Antibodies Targeting the PD-1/PD-L1 Axis.
abstract: Immune checkpoint blockade of the programmed cell death protein 1 (PD-1) pathway by monoclonal antibodies (Abs) has shown promising clinical benefit in the treatment of multiple cancer types. We elucidated the contribution of the fragment crystallizable (Fc) domains of anti-PD-1 and anti-PD-ligand 1 (L1) Abs for their optimal anti-tumor activity. We revealed that distinct Fcγ receptor (FcγRs) dependency and mechanisms account for the in vivo activity of anti-PD-1 versus anti-PD-L1 Abs. Anti-PD-1 Abs were found to be FcγR independent in vivo; the presence of FcγR-binding capacity compromises their anti-tumor activity. In contrast, the anti-PD-L1 Abs show augmented anti-tumor activity when activating FcγR binding is introduced into the molecules, altering myeloid subsets within the tumor microenvironment.
authors.affiliation: Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Rony
authors.initials: R
authors.lastname: Dahan
authors.affiliation: Bristol-Myers Squibb, Biologics Discovery California, Redwood City, CA 94063, USA.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Sega
authors.affiliation: Bristol-Myers Squibb, Biologics Discovery California, Redwood City, CA 94063, USA.
authors.forename: John
authors.initials: J
authors.lastname: Engelhardt
authors.affiliation: Bristol-Myers Squibb, Biologics Discovery California, Redwood City, CA 94063, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Selby
authors.affiliation: Bristol-Myers Squibb, Biologics Discovery California, Redwood City, CA 94063, USA.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Korman
authors.affiliation: Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065, USA. Electronic address: ravetch@rockefeller.edu.
authors.forename: Jeffrey V
authors.initials: JV
authors.lastname: Ravetch
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology*; D060890:B7-H1 Antigen / Q000276:immunology*; D045744:Cell Line, Tumor; D008024:Ligands; D051379:Mice; D009369:Neoplasms / Q000276:immunology*; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology*; D017452:Receptors, IgG / Q000276:immunology*; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: D000906:Antibodies; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D008024:Ligands; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D017452:Receptors, IgG