Phase 1 experience with an anti-glycotope monoclonal antibody, RAV12, in recurrent adenocarcinoma

Howard A. Burris, Lee S. Rosen, Caio M. Rocha-Lima, John Marshall, Suzanne Jones, Roger B. Cohen, Lori A. Kunkel, Deryk Loo, Jan Baughman, Stanford J. Stewart, Nancy Lewis

Research output: Contribution to journalArticle

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Abstract

Purpose: 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 FcγR binding) and to humanize it may improve the toxicity profile and efficacy.

Original languageEnglish
Pages (from-to)1673-1681
Number of pages9
JournalClinical Cancer Research
Volume16
Issue number5
DOIs
StatePublished - Mar 1 2010

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Adenocarcinoma
Monoclonal Antibodies
Pharmacokinetics
Safety
Maximum Tolerated Dose
Liver Function Tests
Abdominal Pain
Primates
Epitopes
Colorectal Neoplasms
Diarrhea
Membrane Proteins
Research Design
Immunoglobulin G
Carbohydrates
Antibodies
Pharmaceutical Preparations
RAAG12

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Burris, H. A., Rosen, L. S., Rocha-Lima, C. M., Marshall, J., Jones, S., Cohen, R. B., ... Lewis, N. (2010). Phase 1 experience with an anti-glycotope monoclonal antibody, RAV12, in recurrent adenocarcinoma. Clinical Cancer Research, 16(5), 1673-1681. https://doi.org/10.1158/1078-0432.CCR-09-2263

Phase 1 experience with an anti-glycotope monoclonal antibody, RAV12, in recurrent adenocarcinoma. / Burris, Howard A.; 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.

In: Clinical Cancer Research, Vol. 16, No. 5, 01.03.2010, p. 1673-1681.

Research output: Contribution to journalArticle

Burris, HA, Rosen, LS, Rocha-Lima, CM, Marshall, J, Jones, S, Cohen, RB, Kunkel, LA, Loo, D, Baughman, J, Stewart, SJ & Lewis, N 2010, 'Phase 1 experience with an anti-glycotope monoclonal antibody, RAV12, in recurrent adenocarcinoma', Clinical Cancer Research, vol. 16, no. 5, pp. 1673-1681. https://doi.org/10.1158/1078-0432.CCR-09-2263
Burris, Howard A. ; 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. / Phase 1 experience with an anti-glycotope monoclonal antibody, RAV12, in recurrent adenocarcinoma. In: Clinical Cancer Research. 2010 ; Vol. 16, No. 5. pp. 1673-1681.
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AU - Burris, Howard A.

AU - Rosen, Lee S.

AU - Rocha-Lima, Caio M.

AU - Marshall, John

AU - Jones, Suzanne

AU - Cohen, Roger B.

AU - Kunkel, Lori A.

AU - Loo, Deryk

AU - Baughman, Jan

AU - Stewart, Stanford J.

AU - Lewis, Nancy

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N2 - Purpose: 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 FcγR binding) and to humanize it may improve the toxicity profile and efficacy.

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