Clinical evaluation of BR96 sFv-PE40 immunotoxin therapy in canine models of spontaneously occurring invasive carcinoma.
OBJECTIVE
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.


METHODS
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/m(2) 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.
Henry
Carolyn J
CJ
Departments of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri-Columbia, 379 East Campus Drive, Columbia, MO 65211, USA. HenryC@missouri.edu
Buss
Michael S
MS
Hellström
Ingegerd
I
Hellström
Karl Erik
KE
Brewer
William G
WG
Bryan
Jeffrey N
JN
Siegall
Clay B
CB
D000818:Animals; D000911:Antibodies, Monoclonal; D004285:Dogs; D005260:Female; D007167:Immunotherapy; D000922:Immunotoxins / Q000627:therapeutic use*; D007983:Lewis Blood Group Antigens / Q000276:immunology / Q000378:metabolism*; D008175:Lung Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D051379:Mice; D009361:Neoplasm Invasiveness / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D011471:Prostatic Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D012004:Rectal Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy
D000911:Antibodies, Monoclonal; C089583:BR96 sFv-PE40; D000922:Immunotoxins; D007983:Lewis Blood Group Antigens; C094162:Lewis Y antigen; D011993:Recombinant Fusion Proteins