title: Phase 1 experience with an anti-glycotope monoclonal antibody, RAV12, in recurrent adenocarcinoma.
abstract: OBJECTIVE
  RAV12 is a high affinity, internalizing, chimeric IgG1 monoclonal antibody that binds RAAG12, a novel primate-restricted N-linked carbohydrate epitope present on multiple cell surface proteins. RAAG12 is highly expressed on many adenocarcinomas, particularly those of gastrointestinal origin. A phase 1 dose-escalation safety and pharmacokinetics trial was conducted in patients with metastatic or recurrent adenocarcinomas.
  
  
  METHODS
  RAV12 was initially given i.v. weekly x4, then by fractionated dosing twice or thrice weekly. Thirty-three patients were treated in the dose escalation segment of the trial in the following cohorts: 0.3 mg/kg qw (6), 1.0 mg/kg qw (8), 1.5 mg/kg qw (7); and 0.5 mg/kg biw (3), 0.75 mg/kg biw (3), and 0.5 mg/kg tiw (6). Twenty patients were enrolled in a maximum tolerated dose cohort expansion at 0.75 mg/kg biw.
  
  
  RESULTS
  Two clinical syndromes were associated with drug administration: abdominal cramping pain with diarrhea, and asymptomatic, self-limited increases of liver function tests. These effects were partially ameliorated with fractionated dosing. Pharmacokinetics was dose dependent. Maximum concentration was reduced, whereas area under the concentration versus time curve was maintained with fractionated dosing. One patient with colorectal cancer experienced a durable partial remission, with a time to progression (TTP) of >8 months. Three additional patients experienced a TTP of >4 months.
  
  
  CONCLUSIONS
  RAV12 has activity in recurrent adenocarcinomas. However, the safety profile of the antibody seems to preclude the delivery of highly efficacious doses. Re-engineering the molecule to remove FcRn binding (while maintaining FcgammaR binding) and to humanize it may improve the toxicity profile and efficacy.
authors.affiliation: Sarah Cannon Research Institute, Nashville, Tenessee 37203-1632, USA. howard.burris@scresearch.net
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
authors.forename: Lee S
authors.initials: LS
authors.lastname: Rosen
authors.forename: Caio M
authors.initials: CM
authors.lastname: Rocha-Lima
authors.forename: John
authors.initials: J
authors.lastname: Marshall
authors.forename: Suzanne
authors.initials: S
authors.lastname: Jones
authors.forename: Roger B
authors.initials: RB
authors.lastname: Cohen
authors.forename: Lori A
authors.initials: LA
authors.lastname: Kunkel
authors.forename: Deryk
authors.initials: D
authors.lastname: Loo
authors.forename: Jan
authors.initials: J
authors.lastname: Baughman
authors.forename: Stanford J
authors.initials: SJ
authors.lastname: Stewart
authors.forename: Nancy
authors.initials: N
authors.lastname: Lewis
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000187:drug effects; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy
chemical_list: D000911:Antibodies, Monoclonal; D015295:Antigens, Tumor-Associated, Carbohydrate; D000970:Antineoplastic Agents; C543696:RAAG12