title: Development of an Fc-enhanced anti-B7-H3 monoclonal antibody with potent antitumor activity.
abstract: OBJECTIVE
  The goal of this research was to harness a monoclonal antibody (mAb) discovery platform to identify cell-surface antigens highly expressed on cancer and develop, through Fc optimization, potent mAb therapies toward these tumor-specific antigens.
  
  
  METHODS
  Fifty independent mAbs targeting the cell-surface immunoregulatory B7-H3 protein were obtained through independent intact cell-based immunizations using human tissue progenitor cells, cancer cell lines, or cell lines displaying cancer stem cell properties. Binding studies revealed this natively reactive B7-H3 mAb panel to bind a range of independent B7-H3 epitopes. Immunohistochemical analyses showed that a subset displayed strong reactivity to a broad range of human cancers while exhibiting limited binding to normal human tissues. A B7-H3 mAb displaying exquisite tumor/normal differential binding was selected for humanization and incorporation of an Fc domain modified to enhance effector-mediated antitumor function via increased affinity for the activating receptor CD16A and decreased binding to the inhibitory receptor CD32B.
  
  
  RESULTS
  MGA271, the resulting engineered anti-B7-H3 mAb, mediates potent antibody-dependent cellular cytotoxicity against a broad range of tumor cell types. Furthermore, in human CD16A-bearing transgenic mice, MGA271 exhibited potent antitumor activity in B7-H3-expressing xenograft models of renal cell and bladder carcinoma. Toxicology studies carried out in cynomolgus monkeys revealed no significant test article-related safety findings.
  
  
  CONCLUSIONS
  This data supports evaluation of MGA271 clinical utility in B7-H3-expressing cancer, while validating a combination of a nontarget biased approach of intact cell immunizations and immunohistochemistry to identify novel cancer antigens with Fc-based mAb engineering to enable potent antitumor activity.
authors.affiliation: MacroGenics, Inc., South San Francisco, CA, USA.
authors.forename: Deryk
authors.initials: D
authors.lastname: Loo
authors.forename: Ralph F
authors.initials: RF
authors.lastname: Alderson
authors.forename: Francine Z
authors.initials: FZ
authors.lastname: Chen
authors.forename: Ling
authors.initials: L
authors.lastname: Huang
authors.forename: Wenjun
authors.initials: W
authors.lastname: Zhang
authors.forename: Sergey
authors.initials: S
authors.lastname: Gorlatov
authors.forename: Steve
authors.initials: S
authors.lastname: Burke
authors.forename: Valentina
authors.initials: V
authors.lastname: Ciccarone
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.forename: Yinhua
authors.initials: Y
authors.lastname: Yang
authors.forename: Tom
authors.initials: T
authors.lastname: Son
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.forename: Ann N
authors.initials: AN
authors.lastname: Easton
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Li
authors.forename: Jill R
authors.initials: JR
authors.lastname: Rillema
authors.forename: Monica
authors.initials: M
authors.lastname: Licea
authors.forename: Claudia
authors.initials: C
authors.lastname: Fieger
authors.forename: Tony W
authors.initials: TW
authors.lastname: Liang
authors.forename: Jennie P
authors.initials: JP
authors.lastname: Mather
authors.forename: Scott
authors.initials: S
authors.lastname: Koenig
authors.forename: Stanford J
authors.initials: SJ
authors.lastname: Stewart
authors.forename: Syd
authors.initials: S
authors.lastname: Johnson
authors.forename: Ezio
authors.initials: E
authors.lastname: Bonvini
authors.forename: Paul A
authors.initials: PA
authors.lastname: Moore
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000276:immunology*; D000954:Antigens, Surface / Q000276:immunology*; D060887:B7 Antigens / Q000276:immunology*; D045744:Cell Line, Tumor; D000939:Epitopes / Q000276:immunology; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000276:immunology; D007167:Immunotherapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D060887:B7 Antigens; C423237:CD276 protein, human; D000939:Epitopes; D007141:Immunoglobulin Fc Fragments