Adriamycin custom-tailored immunoconjugates in the treatment of human malignancies.
Twenty-three patients with disseminated refractory malignancies each received a tailored combination of adriamycin-conjugated murine monoclonal antibodies. Tumors were typed using a panel of antibodies. Cocktails of up to six antibodies were selected based on binding greater than 80% of the malignant cells as tested by immunoperoxidase and flow cytometry. These monoclonal antibodies were then conjugated to Adriamycin and administered intravenously. Seventeen of 23 patients had reactions to the administration of immunoconjugates, but these were tolerable in all but two patients. Fever, chills, pruritus, and skin rash were by far the most common transitory reactions. All were well controlled with premedication. In several patients there was limited antigenic drift among various biopsies within the same patient over time. This observation confirms the necessity for the use of a cocktail of antibodies if one wishes to cover all tumor cells. Preliminary serologic evidence suggests that the development of an IgM antibody, which is specific against the mouse monoclonal antibody, has the specificity and sensitivity to predict clinical reactions. Selected patients were re-treated. One patient with chronic lymphocytic leukemia had re-treatment on three occasions and demonstrated regression of peripheral lymph nodes. Two patients with breast carcinoma had definite improvement in ulcerating skin lesions and two patients with tongue carcinoma had shrinkage of their lesions. In the course of the study free Adriamycin released from the monoclonal antibodies was discovered to be a limiting factor in the amount of antibody that could be administered. Up to 1 g of Adriamycin and up to 5 g of monoclonal antibody were administered. The limiting factor appeared to be a variable dissociation of active Adriamycin from the antibody that unpredictably caused hemopoietic depression. This study demonstrates the feasibility and reviews technical considerations in preparing immunoconjugate cocktails for patients with refractory malignancies. The major technical hurdle appears to be the selection of an effective conjugation method that can be used to optimally bind Adriamycin to monoclonal antibodies for targeted cancer therapy.
Oldham
R K
RK
Williamson Medical Center, Biological Therapy Institute, Franklin, TN 37065-1676.
Lewis
M
M
Orr
D W
DW
Avner
B
B
Liao
S K
SK
Ogden
J R
JR
Avner
B
B
Birch
R
R
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000032:analysis / Q000627:therapeutic use*; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004338:Drug Combinations; D005260:Female; D006801:Humans; D006825:Hybridomas; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology
D000911:Antibodies, Monoclonal; D004338:Drug Combinations; D004317:Doxorubicin