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Clinical Evaluation of BR96 sFv-PE40 Immunotoxin Therapy in Canine Models of Spontaneously Occurring Invasive Carcinoma

¹ Departments of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri-Columbia, Columbia, Missouri; ² Veterinary Clinical Sciences, Washington State University, Pullman, Washington; ³ Small Animal Surgery and Medicine, College of Veterinary Medicine, Auburn University, Auburn, Alabama; and ⁴ Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, Washington

Requests for reprints: Carolyn J. Henry, Departments of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri-Columbia, A373 Clydesdale Hall, 379 East Campus Drive, Columbia, MO 65211. Phone: 573-882-7821; Fax: 573-884-0705; E-mail: HenryC{at}missouri.edu.

Purpose: The immunotoxin BR96 sFv-PE40 is an effective antitumor agent against human breast and lung carcinoma xenografts in rodents. This study was designed to (a) determine the frequency with which canine carcinoma cells express Lewis^y (Le^y) antigen, thereby identifying canine carcinoma types suitable for the clinical evaluation of BR96 sFv-PE40, and (b) determine the safety and efficacy of BR96 sFv-PE40 in a canine model of spontaneously occurring cancers for investigation of targeted therapy.

Experimental Design: Carcinoma tissue samples were obtained from client-owned dogs presented for medical care. The tissues were assessed for Le^y antigen expression using immunohistochemical methods. Dogs with tumors expressing Le^y antigen were offered enrollment in a clinical trial to receive twice-weekly infusions of 4 to 12 mg/m² BR96 sFv-PE40. Clinical toxicity and response data were assessed at each treatment.

Results: Twenty-two of 61 carcinomas evaluated were positive for Le^y expression, including mammary, prostate, lung, and rectal carcinomas, and 12 dogs were enrolled in the clinical trial. The primary side effect was transient emesis. Partial responses or disease stabilization were noted in dogs with inflammatory mammary, bronchogenic, rectal, and tonsillar carcinoma. At least nine of the dogs developed antibodies to the immunotoxin after two to five infusions.

Conclusions: Although development of anti-BR96 sFv-PE40 antibodies limited the long-term effectiveness of this immunotoxin in dogs, rapid clinical responses in several aggressive canine carcinomas suggest the immunotoxin has utility for treatment of certain naturally occurring tumors and that its clinical evaluation for treatment of similar human carcinomas is warranted.

Key Words: inflammatory mammary carcinoma • immunotoxin • Lewis^y antigen • animal model

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