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Comparative clinical pharmacology of [111In]-labeled murine monoclonal antibodies
Abstract:
Patients with metastatic melanoma received either the murine antimelanoma antibody ZME-018 (20 patients) or antibody 96.5 (26 patients) at doses ranging from 1 to 20 mg and coupled to 2.5 or 5 mCi of [111In]. The pharmacokinetics and tissue disposition of these antibodies were measured at various times after infusion of the radiolabel. The clearance of the [111In]label from plasma closely fit (r2 greater than 0.90) an open, one-compartment mathematical model after administration of antibody 96.5. Clearance of [111In] from plasma after administration of ZME-018 fit a one-compartment model in some patients and a two-compartment model in others. The terminal phase half-lives of 96.5 and ZME-018 antibodies at the 20-mg dose were almost identical (27 +/- 2 h and 29 +/- 5 h, respectively). The half-lives calculated for 96.5 were not dependent upon the total antibody dose; however, with increasing doses of ZME-018 there was a dose-dependent increase in t 1/2 (from 17.8 +/- 2 h at the 2.5-mg dose to 29 +/- 5 h at the 20-mg dose). For 96.5 antibody, the apparent volume of distribution (Vd) approximated the total blood volume (7.8 +/- 0.71) at the 1-mg dose and decreased significantly at the 20-mg dose, suggesting saturation of extravascular antigen sites. In contrast, the Vd calculated for ZME-018 did not appear to be dependent upon the administered dose. Improved imaging occurred with increasing doses of unlabeled 96.5 above 2 mg, a finding not observed with ZME-018. The cumulative urine excretion of [111In] after administration of 96.5 or ZME-018 was 10%-14% of the total dose. These studies show that murine monoclonal antibodies of the same subtype but recognizing different surface antigens can exhibit markedly different in vivo pharmacokinetic behavior, which may partially explain differences in imaging noted with increasing doses of monoclonal antibody.
Insights
Murine monoclonal antibodies (mAbs) targeting melanoma showed different pharmacokinetic behaviors. Antibody 96.5 exhibited dose-independent half-lives, while ZME-018 showed dose-dependent clearance, impacting imaging efficacy.
Area of Science:
- Immunotherapy
- Pharmacokinetics
- Oncology
Background:
- Metastatic melanoma treatment involves targeted therapies.
- Murine monoclonal antibodies (mAbs) are investigated for melanoma therapy.
- Understanding mAb pharmacokinetics is crucial for optimizing treatment and imaging.
Purpose of the Study:
- To compare the in vivo pharmacokinetics and tissue disposition of two murine antimelanoma antibodies, ZME-018 and 96.5.
- To investigate the effect of dose on antibody behavior and imaging quality.
- To correlate pharmacokinetic differences with observed imaging outcomes.
Main Methods:
- Patients with metastatic melanoma received radiolabeled ZME-018 or 96.5 antibodies.
- Pharmacokinetics and tissue disposition were measured using [111In]label.
- Mathematical models were used to analyze plasma clearance, half-life, and volume of distribution.
Main Results:
- Antibody 96.5 clearance followed a one-compartment model, while ZME-018 showed one or two-compartment models.
- Terminal half-lives at 20 mg were similar (96.5: 27±2 h, ZME-018: 29±5 h).
- 96.5 half-lives were dose-independent; ZME-018 half-lives increased with dose.
- Volume of distribution for 96.5 decreased significantly at higher doses, suggesting antigen site saturation.
- Improved imaging with 96.5 was observed at doses >2 mg; ZME-018 showed no such improvement.
- Cumulative urine excretion was 10%-14% for both antibodies.
Conclusions:
- Murine monoclonal antibodies of the same subtype can exhibit distinct in vivo pharmacokinetic profiles.
- Differences in pharmacokinetics, particularly dose-dependency, may explain variations in imaging efficacy.
- These findings highlight the importance of individualized pharmacokinetic assessment for antibody-based therapies.