Phase I clinical and pharmacological study of suppression of human antimouse antibody response to monoclonal antibody L6 by deoxyspergualin.
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 (antiisotypic 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.
Dhingra
K
K
Department of Breast Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Fritsche
H
H
Murray
J L
JL
LoBuglio
A F
AF
Khazaeli
M B
MB
Kelley
S
S
Tepper
M A
MA
Grasela
D
D
Buzdar
A
A
Valero
V
V
D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D000888:Antibodies, Anti-Idiotypic / Q000096:biosynthesis*; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000187:drug effects* / Q000494:pharmacology*; D000917:Antibody Formation / Q000187:drug effects; D003167:Complement Activation / Q000187:drug effects; D003176:Complement C3 / Q000378:metabolism; D003181:Complement C4 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006146:Guanidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007519:Isoantigens / Q000276:immunology / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology*
D000903:Antibiotics, Antineoplastic; D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D003176:Complement C3; D003181:Complement C4; D006146:Guanidines; D007519:Isoantigens; C037258:gusperimus