This is an archive of papers published by the staff and faculty of Fox Chase Cancer Center. For questions about content, please contact Talbot Research Library
Last updated on
Burris HA , Rosen LS , Rocha-Lima CM , Marshall J , Jones S , Cohen RB , Kunkel LA , Loo D , Baughman J , Stewart SJ , Lewis N
Phase 1 Experience with an Anti-Glycotope Monoclonal Antibody, RAV12, in Recurrent Adenocarcinoma
Clinical Cancer Research. 2010 Mar;16(5) :1673-1681
AbstractPurpose: 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. Experimental Design: 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 Fc gamma R binding) and to humanize it may improve the toxicity profile and efficacy. Clin Cancer Res; 16(5); 1673-81. (C) 2010 AACR.
NotesBurris, Howard A., III Rosen, Lee S. Rocha-Lima, Caio M. Marshall, John Jones, Suzanne Cohen, Roger B. Kunkel, Lori A. Loo, Deryk Baughman, Jan Stewart, Stanford J. Lewis, Nancy Raven biotechnologies, Inc. ; MacroGenics, Inc. Grant Support Raven biotechnologies, Inc., now MacroGenics, Inc. 12 Amer assoc cancer research; 615 chestnut st, 17th floor, philadelphia, pa 19106-4404 usa 607zj