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Phase I Clinical and Pharmacological Study of Suppression of Human Antimouse Antibody Response to Monoclonal Antibody L6 by Deoxyspergualin¹

Departments of Breast Medical Oncology [K. D., A. B., V. V., D. B., H. W., G. H.], Laboratory Medicine [H. F.], and Clinical Immunology and Biological Therapy [J. L. M.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030; Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama 35294 [A. F. L., M. B. K.]; and Departments of Cancer Clinical Research [S. K., M. A. T.] and Human Pharmacology [D. G., T. J. C., J. M. P.], Bristol-Myers Squibb Company, Wallingford, Connecticut 06492

Development of human antimouse antibody (HAMA) is a major limiting factor in the application of murine mAb for clinical use. A novel immunomodulatory drug, deoxyspergualin (DSG), has shown potential to suppress antimouse antibody response in preclinical model systems. We conducted a Phase I trial to determine the effect of DSG on HAMA response to murine mAb L6 administered to patients with advanced cancers (in previous trials, this antibody elicited HAMA in two-thirds of the treated patients). L6 mAb was administered at a fixed dose of 200 mg/m² on days 1–5. DSG was administered at doses of 50 mg/m² [dose level (dl) 1] or 150 mg/m² (dls II and III) on days 1–7. Treatment courses were repeated every 6 weeks (dls I and II) or every 3 weeks (dl III). HAMAs were quantitated by a commercially available ELISA assay (ImmuSTRIP; anti-isotypic antibodies) and a radiometric assay (anti-isotypic and anti-idiotypic antibodies). Pharmacokinetics of L6 and DSG was also studied in all consenting patients. Among 24 evaluable patients, 2 patients developed detectable HAMAs using the ELISA (one each at dls I and II) after a median follow-up of 122 days (P = 0.0001 as compared to historical controls). Even in the two patients who developed HAMA, the HAMA levels were quite low (160 and 181 ng/ml; historical experience, 70–38,744 ng/ml). The radiometric assay detected anti-L6 antibodies in 13 patients (4, 6, and 3 at dls I–III, respectively) after a median of 82 days. The median highest anti-L6 antibody level was 129 ng/ml (range, 21–2150). The highest anti-L6 antibody level at dl III was only 44 ng/ml. The results suggest suppression of anti-idiotypic response also. No clinical antitumor activity was observed, and no significant changes in T4/T8 subsets or immunoglobulins occurred (suggesting a lack of generalized immunosuppression). We conclude that DSG can suppress HAMA response to L6. A starting dose of 150 mg/m²/day is recommended for Phase II trials to confirm this observation.

¹ Supported in part by the Bristol-Myers Squibb Company and the National Cancer Institute. K. D. is a recipient of a Clinical Oncology Career Development Award from the American Cancer Society. Preliminary results of this trial were presented at the 5th International Workshop on Breast Cancer Research and Immunology, November 1992, and the Annual Meeting of the American Society for Clinical Oncology, May 1993.

² To whom requests for reprints should be addressed, at Department of Breast Medical Oncology, Box 56, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030.

Received 2/ 3/95. Accepted 5/12/95.

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